Piperidin-2-one derivative compounds and drugs containing these compounds as the active ingredient

ABSTRACT

A piperidin-2-one derivative compound represented by formula (I):  
                 
wherein all symbols are described in the specification, or a non-toxic salt thereof. The compound represented by formula (I) inhibits activation of p38MAP kinase, and is useful for prevention and/or treatment of various inflammatory diseases, rheumatoid arthritis, osteoarthritis, arthritis, osteoporosis, autoimmune diseases, infectious diseases, sepsis, cachexia, cerebral infarction, Alzheimer&#39;s disease, asthma, chronic pulmonary inflammatory diseases, reperfusion injury, thrombosis, glomerulonephritis, diabetes, graft versus host rejection, inflammatory bowel disease, Crohn&#39;s disease, ulcerative colitis, multiple sclerosis, tumor growth and metastasis, multiple myeloma, plasma cell leukemia, Castleman&#39;s disease, atrial myxoma, psoriasis, dermatitis, gout, adult respiratory distress syndrome (ARDS), arteriosclerosis, post-percutaneous transluminal coronary angioplasty (PTCA) restenosis or pancreatitis.

TECHNICAL FIELD

The present invention relates to piperidin-2-one derivatives.

Particularly, the present invention relates to

-   (1) a piperidin-2-one derivatives represented by formula (I)    (wherein all symbols have tha same meanings as described below)    or a non-toxic salt thereof,-   (2) a method for preparation of the same, and-   (3) a pharmaceutical composition comprising the same as an active    ingredient.

BACKGROUND ART

p38 mitogen-activated protein (MAP) kinase (p38α/Mpk2/RK/SAPK2a/CSBP)(hereinafter referred to as “p38MAP kinase”) was cloned as an enzymewhich induces tyrosine phosphorylation in monocyte after stimulationwith lipopolysaccharide (LPS) (Nature, 372, 739 (1994)), and isactivated by various extracellular stimuli (physical stimuli: osmoticshock, heat shock, UV irradiation, chemical stimuli: endotoxin, hydrogenperoxide, arsenic trioxide, an inflammatory cytokine and a growthfactor). Also, since p38MAP kinase relates to the production of aninflammatory cytokine and chemokine such as tumor necrosis factor-α(TNF-α), interleukin 1 (IL-1), IL-6 or IL-8, an association between theactivation of this enzyme and diseases is strongly suggested. Therefore,an improvement effect on various disease symptoms represented byinflammatory diseases is expected by the suppression of p38MAP kinaseactivation.

Accordingly, a p38MAP kinase inhibitor is expected to be useful in theprevention and/or the treatment of diseases whose cause or deteriorationis thought to be related to the abnormal production of an inflammatorycytokine or chemokine or over response to them, such as variousinflammatory diseases, rheumatoid arthritis, osteoarthritis, arthritis,osteoporosis, autoimmune diseases, infectious diseases, sepsis,cachexia, cerebral infarction, Alzheimer's disease, asthma, chronicpulmonary inflammatory diseases, reperfusion injury, thrombosis,glomerulonephritis, diabetes, graft versus host rejection, inflammatorybowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis,tumor growth and metastasis, multiple myeloma, plasma cell leukemia,Castleman's disease, atrial myxoma, psoriasis, dermatitis, gout, adultrespiratory distress syndrome (ARDS), arteriosclerosis,post-percutaneous transluminal coronary angioplasty (PTCA) restenosisand pancreatitis.

As p38MAP kinase inhibitors, for example, WO99/64400 discloses thatcompounds shown by formulae (A) to (G) are useful for p38MAP kinaseinhibitors:

-   -   wherein Q^(1A) and Q^(2A) each independently is selected from a        5- to 6-membered aromatic carbocyclic ring, a heterocyclic ring        and the like;    -   Q^(1A) each independently is substituted with 1 to 4        substituent(s) selected from a halogen atom, C₁-C₃ alkyl        optionally substituted with NR′₁₂, OR′, CO₂R′ or CONR′₂, and the        like;    -   Q^(2A) each independently is substituted with at most 4        substituent(s) selected from halogen or C₁-C₃ straight-chain or        branched alkyl optionally substituted with NR′₂, OR′, CO₂R′,        S(O₂)N(R′)₂, N═C—N(R′)₂, R³ or CONR′₂;    -   X^(A), when present, is selected from —S—, —O—, —N(R²)—, and the        like;    -   R^(1A) is selected from a hydrogen atom, (C₁-C₃) alkyl, OH or        O—(C₁-C₃) alkyl;    -   wherein necessary ones of the symbols in the groups are        extracted.

Also, DE10002509 discloses that compounds represented by formula byformula (H) are useful as IL-12 inhibitors:

-   -   wherein R^(1B) and R^(2B) each represents a hydrogen atom, a        chlorine atom, a fluorine atom, OH, or the like;    -   R^(3B) represents a hydrogen atom, OH, or CH₂NR^(6B)R^(7B);    -   R^(6B) and R^(7B), taken together, form pyrrolidine, piperidine,        morpholine, or the like;    -   R^(4B) represents a hydrogen atom, C1-3 alkyl, a fluorine atom,        trifluoromethyl, or difluoromethyl.

X^(B) represents (CH₂)_(n)—NR^(8B), (CH₂)_(n)—S, (CH₂)_(q), or the like,

-   -   wherein necessary ones of the symbols in the groups are        extracted.

DISCLOSURE OF THE INVENTION

As a result of the present inventors intensively studied to findcompounds which are useful as agents for treatment of diseases bysuppressing the activity of p38MAP as the subject, they found that theobject was accomplished by novel piperidin-2-one derivatives representedby the following formula (I), and thus the present invention has beencompleted.

That is, the present invention relates to[1] a piperidin-2-one derivative compound represented by formula (I):

-   -   wherein ring A represents a C5-10 mono- or bi-carbocyclic ring,        or a 5- to 10-membered mono- or bi-heterocyclic ring having 1 to        5 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom;    -   R¹ represents

-   (1) C1-8 alkyl,

-   (2) C2-8 alkenyl,

-   (3) C2-8 alkynyl,

-   (4) a halogen atom,

-   (5) —OR⁴,

-   (6) —NR⁵R⁶,

-   (7) —NR⁷COR⁸,

-   (8) —CONR⁹R¹⁰,

-   (9) —COOR¹¹,

-   (10) —SO₂NR¹²R¹³,

-   (11) —NR¹⁴SO₂R¹⁵,

-   (12) —SR¹⁶,

-   (13) —S(O)R¹⁷,

-   (14) —SO₂R¹⁸,

-   (15) —NR²²COOR²³,

-   (16) —NR²⁴CONR²⁵R²⁶,

-   (17) —COR²⁷,

-   (18) —NO₂,

-   (19) —CN,

-   (20) —CF₃,

-   (21) —OCF₃,

-   (22) Cyc1, or

-   (23) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to    5 substituent(s) selected from the group consisting of (a) a halogen    atom, (b) —OR⁴, (c) —NR⁵R⁶, (d) —NR⁷COR⁸, (e) —CONR⁹R¹⁰, (f)    —COOR¹¹, (g) —SO₂NR¹²R¹³, (h) —NR¹⁴SO₂R¹⁵, (i) —SR¹⁶, (j)    —S(O)R¹⁷, (k) —SO₂R¹⁸, (l) —NR²²COOR²³, (m) —NR²⁴CONR²⁵R²⁶, (n)    —COR²⁷, (o) —NO₂, (p) —CN, (q) —CF₃, (r) —OCF₃, and (s) Cyc1;    -   R⁴-R¹⁸ or R²²-R²⁷ each independently represents

-   (1) a hydrogen atom,

-   (2) C1-8 alkyl,

-   (3) Cyc1, or

-   (4) C1-8 alkyl substituted with 1 to 5 substituent(s) selected from    the group consisting of (a) —OR²⁸, (b) —NR²⁹R³⁰ (c) —NR³¹COR³², (d)    —CONR³³R³⁴, (e) (f) —SO₂NR³⁶R³⁷, (g) —NR³⁸SO₂R³⁹, (h)    —CONR⁴⁰NR⁴¹R⁴², (i) —CONR⁴³ OR⁴⁴, and (j) Cyc1,    -   R²⁸-R⁴⁴ each independently represents

-   (1) a hydrogen atom,

-   (2) C1-8 alkyl,

-   (3) Cyc1, or

-   (4) C1-8 alkyl substituted with 1 to 5 substituent(s) selected from    the group consisting of —OR⁴⁵, —NR⁴⁶R⁴⁷, and Cyc1;    -   R⁴⁵-R⁴⁷ each independently represents a hydrogen atom, C1-8        alkyl, Cyc1, or C1-8 alkyl substituted with Cyc1;    -   Cyc1 represents a C5-10 mono- or bi-carbocyclic ring or a 5- to        10-membered mono- or bi-heterocyclic ring having 1 to 5 nitrogen        atom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom, in which        the carbocyclic ring or the heterocyclic ring may be substituted        with 1 to 5 of R⁴⁸;    -   R⁴⁸ represents

-   (1) C1-8 alkyl,

-   (2) a halogen atom,

-   (3) —NO₂,

-   (4) —CN,

-   (5) —OR⁴⁹,

-   (6) —NR⁵⁰R⁵¹,

-   (7) —COOR⁵²,

-   (8) —COR⁵³,

-   (9) —CONR⁵⁴R⁵⁵,

-   (10) —NR⁵⁶COR⁵⁷,

-   (11) —SO₂NR⁵⁸R⁵⁹,

-   (12) —NR⁶⁰SO₂R⁶¹,

-   (13) —SR⁶²,

-   (14) —SO₂R⁶³,

-   (15) oxo,

-   (16) —CF₃,

-   (17) —OCF₃, or

-   (18) C1-8 alkyl substituted with 1 to 5 substituent(s) selected from    the group consisting of (a) a halogen atom, (b) —NO₂, (c) —CN, (d)    —OR⁴⁹, (e) —NR⁵⁰R⁵¹, (f) —COOR⁵², (g) —COR⁵³, (h) —CONR⁵⁴R⁵⁵, (i)    —NR⁵⁶COR⁵⁷, (j) —SO₂NR⁵⁸R⁵⁹, (k) —NR⁶⁰SO₂R⁶¹, (l) —SR⁶², (m)    —SO₂R⁶³, (n) oxo, (o) —CF₃, and (p) —OCF₃;    -   R⁴⁹-R⁶³ each independently represents, a hydrogen atom, C1-8        alkyl, phenyl, or C₁-8 alkyl substituted with phenyl;    -   R² represents

-   (1) C1-8 alkyl,

-   (2) —OR²⁰,

-   (3) —NR⁶⁴R⁶⁵,

-   (4) —COOR⁶⁶,

-   (5) —CONR⁶⁷R⁶⁸,

-   (6) —NR⁶⁹COR⁷⁰,

-   (7) —SO₂R⁷¹,

-   (8) —SO₂NR⁷²R⁷³,

-   (9) —NR⁷⁴SO₂R⁷⁵,

-   (10) —NR⁷⁶COOR⁷⁷,

-   (11) Cyc2, or

-   (12) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to    5 substituent(s) selected from the group consisting of (a)    —OR²⁰, (b) —NR⁶⁴R⁶⁵, (c) —COOR⁶⁶, (d) —CONR⁶⁷R⁶⁸, (e)    —NR⁶⁹COR⁷⁰, (f) —SO₂R⁷¹, (g) —SO₂NR⁷²R⁷³, (h) —NR⁷⁴SO₂R⁷⁵, (i)    NR⁷⁶COOR⁷⁷, and (j) Cyc2;    -   R²⁰ and R⁶⁴-R⁷⁷ each independently represents (1) a hydrogen        atom, (2) C1-8 alkyl, (3) Cyc2 or (4) C1-8 alkyl substituted        with Cyc2;    -   Cyc2 represents a C5-6 monocarbocyclic ring, or a 5- to        6-membered monoheterocyclic ring having 1 to 4 nitrogen atom(s),        1 to 2 oxygen atom(s) and/or a sulfur atom, in which the        carbocyclic ring or the heterocyclic ring may be substituted        with 1 to 5 substituent(s) selected from the group consisting of        C1-8 alkyl, C1-8 alkoxy, a halogen atom, —CF₃ and OCF₃;    -   G or J each independently represents, a carbon atom, a nitrogen        atom, an oxygen atom, or a sulfur atom;    -   E represents C1-4 alkylene, C2-4 alkenylene, —O—, —S—, —NR²¹—,        —NR⁷⁹SO₂— or —SO₂NR⁸⁰—, in which the C1-4 alkylene may be        substituted with 1 to 5 of C1-8 alkyl, C1-8 alkoxy, a halogen        atom, or hydroxyl;    -   R²¹ and R⁷⁸-R⁸⁰ each independently represents (1) a hydrogen        atom, (2) C1-8 alkyl, (3) Cyc3, or (4) C1-8 alkyl substituted        with 1 to 5 of Cyc3 or hydroxyl;    -   Cyc3 represents a C5-6 monocarbocyclic ring, or a 5- to        6-membered monoheterocyclic ring having 1 to 4 nitrogen atom(s),        1 to 2 oxygen atom(s) and/or a sulfur atom, in which the        carbocyclic ring or the heterocyclic ring may be substituted        with 1 to 5 of C1-8 alkyl, C1-8 alkoxy, a halogen atom, —CF₃ or        OCF₃;    -   Ring B represents a C5-10 mono- or bi-carbocyclic ring, or a 5-        to 10-membered mono- or bi-heterocyclic ring having 1 to 4        nitrogen atom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom;    -   R³ represents

-   (1) C1-8 alkyl,

-   (2) C2-8 alkenyl,

-   (3) C2-8 alkynyl,

-   (4) a halogen atom,

-   (5) —OR⁸¹,

-   (6) —NR⁸²R⁸³,

-   (7) —NR⁸⁴COR⁸⁵,

-   (8) —CONR⁸⁶R⁸⁷,

-   (9) —COOR⁸⁸,

-   (10) —SO₂NR⁸⁹R⁹⁰,

-   (11) —NR⁹¹SO₂R⁹²,

-   (12) —SR⁹³,

-   (13) —S(O)R⁹⁴,

-   (14) —SO₂R⁹⁵,

-   (15) —NR⁹⁶COOR⁹⁷,

-   (16) —NR⁹⁸CONR⁹⁹R¹⁰⁰,

-   (17) —OCONR¹⁰¹R¹⁰²,

-   (18) —NO₂,

-   (19) —CN,

-   (20) —CF₃,

-   (21) —OCF₃,

-   (22) Cyc4, or

-   (23) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to    5 substituent(s) selected from the group consisting of (a) a halogen    atom, (b) —OR⁸¹, (c) —NR⁸²R⁸³, (d) —NR⁸⁴COR⁸⁵, (e) —CONR⁸⁶R⁸⁷, (f)    —COOR⁸⁸, (g) —SO₂NR⁸⁹R⁹⁰, (h) —NR⁹¹SO₂R⁹², (i) —SR⁹³, (j)    —S(O)R⁹⁴, (k) —SO₂R⁹⁵, (l) —NR⁹⁶COOR⁹⁷, (m) —NR⁹⁸CONR⁹⁹R¹⁰⁰, (n)    —OCONR¹⁰¹R¹⁰², (o) —NO₂, (p) —CN, (q) —CF₃, (r) —OCF₃, and (s) Cyc4;    -   R⁸¹-R¹⁰² each independently represents (1) a hydrogen atom, (2)        C1-8 alkyl, (3) Cyc4 or (4) C1-8 alkyl substituted with 1 to 5        substituent(s) selected from the group consisting of Cyc4,        —OR¹⁰³, —CONR¹⁰⁴R¹⁰⁵, and —COOR¹⁰⁶;    -   R¹⁰³-R¹⁰⁶ each independently represents, (1) a hydrogen        atom, (2) C1-8 alkyl, (3) Cyc4 or (4) C1-8 alkyl substituted        with 1 to 5 substituent(s) selected from Cyc4 and —OR¹⁰⁷;    -   R¹⁰⁷ represents (1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc4        or (4) C1-8 alkyl substituted with Cyc4;    -   Cyc4 is a C5-10 mono- or bi-carbocyclic ring, or a 5- to        10-membered mono- or bi-heterocyclic ring having 1 to 5 nitrogen        atom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom, in which        the carbocyclic ring or the heterocyclic ring may be substituted        with 1 to 5 of C1-8 alkyl, C1-8 alkoxy, a halogen atom, —CF₃ or        —OCF₃;    -   m represents 0 or an integer of 1 to 5;    -   n represents 0 or an integer of 1 to 7;    -   i represents 0 or an integer of 1 to 12,    -   wherein

-   (1) when m is 2 or more, R¹ is the same or different,

-   (2) when n is 2 or more, R² is the same or different,

-   (3) when i is 2 or more, R³ is the same or different,

-   (4) when E is C1-4 alkylene,    is a single bond or a double bond,

-   (5) when E is other than C1-4 alkylene,    is a single bond,    -   or a non-toxic salt thereof,        [2] a process for producing the same, and        [3] a pharmaceutical composition comprising the same as an        active ingredient.

In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl or isomeric groups thereof.

C2-8 alkenyl means ethenyl, propenyl, butenyl, butadienyl, pentenyl,pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl,octadienyl or isomeric groups thereof.

C2-8 alkynyl means ethynyl, propynyl, butynyl, butadiynyl, pentynyl,pentadiynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl,octadiynyl or isomeric groups thereof.

C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy or isomeric groups thereof.

C1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene orisomeric groups thereof.

C2-4 alkenylene means ethenylene, propenylene, butenylene or isomericgroups thereof.

Halogen atom means chlorine, bromine, fluorine and iodine atom.

C5-10 mono- or bi-carbocyclic ring means, for example, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene,perhydropentalene, azulene, perhydroazulene, indene, perhydroindene,indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene, etc.

C5-6 monocarbocyclic ring means, for example, cyclopentane, cyclohexane,cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene,etc.

5- to 10-membered monoheterocyclic ring containing 1-5 nitrogen atom(s),1-2 oxygen atom(s) and/or 1 sulfur atom means 5- to 10-memberedmonocyclic heteroaryl containing 1-5 nitrogen atom(s), 1-2 oxygenatom(s) and/or 1 sulfur atom, and partially or fully saturated one. Itincludes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine,oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, thiadiazepine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, etc.

5- to 10-membered biheterocyclic ring containing 1-5 nitrogen atom(s),1-2 oxygen atom(s) and/or 1 sulfur atom means 5- to 10-membered bicyclicheteroaryl containing 1-5 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1sulfur atom, and partially or fully saturated one. It includes, forexample, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,chromene, benzofurazan, benzothiadiazole, benzotriazole, benzofurazan,benzothiadiazole, benzotriazole, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dioxaindan, benzodioxane,chroman, etc.

5- to 6-membered monoheterocyclic ring containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1 sulfur atom means 5- to 6-memberedmonocyclic heteroaryl containing 1-4 nitrogen atom(s), 1-2 oxygenatom(s) and/or 1 sulfur atom, and partially or fully saturated one. Itincludes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran,thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine,thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine,oxathiane, dioxolane, dioxane, etc.

In the present invention, all isomers are included unless otherwisespecified. For example, alkyl, alkoxy and alkylene group includesstraight or branched ones. In addition, isomers on double bond, ring,fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, l-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

In the present invention, unless otherwise indicated and as is apparentfor those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-, β- or a mixture thereof, and symbol

indicates that it is a mixture of α-configuration and β-configuration.

[Salt]

In the present invention, non-toxic salts include all pharmaceuticallyacceptable salts. It includes, for example, general salts, acid additionsalts, etc.

The compounds represented by formula (I) of the present invention may beconverted into the corresponding salts by conventional means. Non-toxicand water-soluble salts are preferred. Suitable salts, for example,include; salts of alkali metals (e.g. potassium, sodium, etc.), salts ofalkaline earth metals (e.g. calcium, magnesium, etc.), ammonium salts,salts of pharmaceutically acceptable organic amines (e.g.tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine, etc.), etc.

The compounds represented by formula (I) of the present invention may beconverted into the corresponding acid addition salts by conventionalmeans. Non-toxic and water-soluble salts are preferred. Suitable acidaddition salts, for example, include; salts of inorganic acids e.g.hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc.; salts oforganic acids e.g. acetate, trifluoroacetate, lactate, tartrate,oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate,glucuronate, gluconate, etc.

The compounds represented by formula (I) of the present invention or thesalts thereof may be converted into the corresponding solvates byconventional means.

Non-toxic and water-soluble solvates are preferred. Suitable solvatesinclude, for example, hydrates, solvates of the alcohols (e.g. ethanoletc.), etc.

In the present invention, all groups represented by R¹, R² and R³ arepreferred.

In formula (I), R¹ is preferably C1-8 alkyl, a halogen atom, —NR⁵R⁶,—NR⁷COR⁸, —COOR¹¹, —SO₂NR¹²R¹³, —NR¹⁴SO₂R¹⁵ or C1-4 alkyl substitutedwith OR⁴, more preferably C1-4 alkyl, a halogen atom, —NR⁵R⁶ or—NR⁷COR⁸, and most preferably methyl, ethyl, a fluorine atom or achlorine atom.

In formula (I), R² is preferably C1-8 alkyl, —OR²⁰, —COOR⁶⁶ or C1-4alkyl substituted with Cyc2, more preferably C1-4 alkyl, —OR²⁰ or—COOR⁶⁶, and most preferably methyl, ethyl, hydroxyl, methoxy, —COOH or—COOCH₃.

In formula (I), R³ is preferably C1-8 alkyl, a halogen atom, —OR⁸¹,—NR⁹⁸CONR⁹⁹R¹⁰⁰, —OCONR¹⁰¹R¹⁰², C1-8 alkyl substituted with—NR⁹⁸CONR⁹⁹R¹⁰⁰, or C1-8 alkyl substituted with —OCONR¹⁰¹R¹⁰², morepreferably C1-4 alkyl, a halogen atom, C1-4 alkyl substituted with—NR⁹⁸CONR⁹⁹R¹⁰⁰, or C1-4 alkyl substituted with —OCONR¹⁰¹R¹⁰², and mostpreferably methyl, a fluorine atom, a chorine atom, —CH₂—NR⁹⁸CONR⁹⁹R¹⁰⁰or —CH₂—OCONR¹⁰¹R¹⁰².

In formula (I), the ring A is preferably a C5-10 mono- or bi-carbocyclicring or a mono- or bi-heterocyclic ring having 1 to 2 nitrogen atom(s),1 to 2 oxygen atom(s) and/or a sulfur atom, more preferably a C5-6monocarbocyclic ring, or a 5- to 6-membered monocyclic heteroaryl having1 to 2 nitrogen atom(s), an oxygen atom and/or a sulfur atom, and mostpreferably a benzene ring, a pyridine ring, a thiophene ring, or acyclohexane ring.

In formula (I), the ring B is preferably a C5-10 mono- or bi-carbocyclicring, and most preferably a benzene ring or a naphthalene ring.

In formula (I), G is preferably a carbon atom, a nitrogen atom, anoxygen atom, or a sulfur atom.

In formula (I), J is preferably a carbon atom, an oxygen atom, or asulfur atom.

In formula (I), E is preferably C1-4 alkylene, C1-4 alkylene substitutedwith hydroxyl, C1-4 alkylene substituted with C1-4 alkoxy, —S— or

and most preferably methylene, hydroxymethylene, methoxymethylene, orhydroxyiminomethylene.

In formula (I), m is preferably 0 or an integer of 1 to 3.

In formula (I), n is preferably 0 or an integer of 1 to 3.

In formula (I), i is preferably 0 or an integer of 1 to 3.

In the present invention, when m is 2 or more, n is 2 or more, and i is2 or more, each of R¹, each of R² and each of R³, respectively, is thesame or different.

In formula (I), Cyc1 is preferably a C5-6 monocarbocyclic ring, or a 5-to 6-membered monoheterocyclic ring having 1 to 5 nitrogen atom(s), 1 to2 oxygen atom(s) and/or a sulfur atom; more preferably C5-6monocarbocyclic ring, and most preferably a benzene ring.

In formula (I), Cyc2 is preferably a C5-6 monocarbocyclic ring, or a 5-6membered monocyclic hetero ring having 1 to 4 nitrogen atom(s), 1 to 2oxygen atom(s) and/or a sulfur atom, more preferably a C5-6monocarbocyclic ring, and most preferably a benzene ring.

In formula (I), Cyc3 is preferably a C5-6 monocarbocyclic ring, or a 5-to 6-membered monoheterocyclic ring having 1 to 4 nitrogen atom(s), 1 to2 oxygen atom(s) and/or a sulfur atom, and most preferably a benzenering.

Among the compounds represented by formula (I), preferred compoundsincludes:a compound represented by formula (I-A-1):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-A-2):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-A-3):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-A-4):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-B-1):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-B-2):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-B-3):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-B-4):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-C-1):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-C-2):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-C-3):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-C-4):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-D-1):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-D-2):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-D-3):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-D-4):

(wherein all symbols in the formula have the same meanings as definedabove),a compound represented by formula (I-E-1):

(wherein all symbols in the formula have the same meanings as definedabove),and a compound represented by formula (I-E-2):

(wherein all symbols in the formula have the same meanings as definedabove).

Specific preferred compounds of the present invention includes compoundsshown in Tables 1 to 42, compounds described in Examples, and non-toxicsalts thereof.

In Tables, Ph represents phenyl, and other symbols have the samemeanings as defined above. TABLE 1 (I-A-1-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 2 (I-A-1-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 3 (I-B-1-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 4 (I-B-1-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 5 (I-C-1-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 6 (I-C-1-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 7 (I-A-2-1)

No. R¹ 1 H 2 4-OH 3 4-CH₂OH 4 4-NH₂ 5 4-NHCH₃ 6 4-NHCOCH₃ 7 4-NHCOCH₂Ph8 5-OH 9 5-CH₂OH 10 5-NH₂ 11 5-NHCH₃ 12 5-NHCOCH₃ 13 5-NHCOCH₂Ph

TABLE 8 (I-A-2-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 9 (I-B-2-1)

No. R¹ 1 H 2 4-OH 3 4-CH₂OH 4 4-NH₂ 5 4-NHCH₃ 6 4-NHCOCH₃ 7 4-NHCOCH₂Ph8 5-OH 9 5-CH₂OH 10 5-NH₂ 11 5-NHCH₃ 12 5-NHCOCH₃ 13 5-NHCOCH₂Ph

TABLE 10 (I-B-2-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 11 (I-C-2-1)

No. R¹ 1 H 2 4-OH 3 4-CH₂OH 4 4-NH₂ 5 4-NHCH₃ 6 4-NHCOCH₃ 7 4-NHCOCH₂Ph8 5-OH 9 5-CH₂OH 10 5-NH₂ 11 5-NHCH₃ 12 5-NHCOCH₃ 13 5-NHCOCH₂Ph

TABLE 12 (I-C-2-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 13 (I-A-2-3)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 14 (I-A-2-4)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 15 (I-B-2-3)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 16 (I-B-2-4)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 17 (I-C-2-3)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 18 (I-C-2-4)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 19 (I-A-3-1)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 20 (I-A-3-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 21 (I-B-3-1)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 22 (I-B-3-2)

 No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 23 (I-C-3-1)

No. R¹ 1 H 2 OH 3 CH₂OH 4 NH₂ 5 NHCH₃ 6 NHCOCH₃ 7 NHCOCH₂Ph

TABLE 24 (I-C-3-2)

 No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 25 (I-A-4-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 26 (I-A-4-2)

 No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 27 (I-B-4-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 28 (I-B-4-2)

 No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 29 (I-C-4-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 30 (I-C-4-2)

 No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 31 (I-D-1-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 32 (I-D-1-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 33 (I-D-2-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 34 (I-D-2-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 35 (I-D-3-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 36 (I-D-3-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 37 (I-D-4-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 38 (I-D-4-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 39 (I-E-1-1)

No. R¹ 1 H 2 3-OH 3 3-CH₂OH 4 3-NH₂ 5 3-NHCH₃ 6 3-NHCOCH₃ 7 3-NHCOCH₂Ph8 4-OH 9 4-CH₂OH 10 4-NH₂ 11 4-NHCH₃ 12 4-NHCOCH₃ 13 4-NHCOCH₂Ph

TABLE 40 (I-E-1-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 41 (I-E-2-1)

No. R¹ No. R¹ 1 H 8 4-OH 2 3-OH 9 4-CH₂OH 3 3-CH₂OH 10 4-NH₂ 4 3-NH₂ 114-NHCH₃ 5 3-NHCH₃ 12 4-NHCOCH₃ 6 3-NHCOCH₃ 13 4-NHCOCH₂Ph 7 3-NHCOCH₂Ph

TABLE 42 (I-E-2-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

[Method for Preparing Compounds of the Present Invention]

The compound represented by formula (I) of the present invention can beproduced by the following method or the method described in Examples.[A] Among the compounds represented by formula (I) of the presentinvention, a compound wherein

represents a single bond, i.e., a compound represented by formula (I-A):

(wherein all symbols have the same meanings as defined above) can beproduced by the following method.[1] The compound represented by formula (I-A) can be produced bysubjecting a compound represented by formula (II):

(wherein X represents a leaving group (e.g., chlorine atom, bromineatom, iodine atom, tosyl, mesyl) and R¹⁻¹, R²⁻¹, R³⁻¹ and E¹ have thesame meanings as R¹, R², R³, and E, respectively, wherein hydroxyl,amino, thiol or carboxyl contained in the group represented by R¹⁻¹,R²⁻¹, R³⁻¹ or E¹ is optionally protected, if necessary, and othersymbols have the same meanings as defined above) to a cyclizationreaction to thereby give a compound represented by formula (I-1):

(wherein all symbols have the same meanings as defined above), followedby a deprotection reaction of a protective group, if necessary.

The cyclization reaction of the compound represented by formula (II) isknown, and for example, can be carried out by reacting the compoundrepresented by formula (II) in an organic solvent (diethyl ether,tetrahydrofuran, etc.) in the presence of a base (tert-butoxy potassium,sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride,etc.) at a temperature of −20 to 40° C.

The deprotection reaction of a protective group can be carried out bythe following method.

The deprotection reaction of a protective group for hydroxyl, amino,thiol or carboxyl is known and it includes

-   (1) alkaline hydrolysis,-   (2) deprotection reaction under acidic conditions,-   (3) deprotection reaction by hydrogenolysis,-   (4) deprotection reaction of a silyl group,    and the like.

These methods are described specifically as follows.

-   (1) The deprotection reaction by alkaline hydrolysis is, for    example, carried out in an organic solvent (methanol,    tetrahydrofuran, dioxane, or a mixture thereof, etc.) using a    hydroxide of an alkali metal (sodium hydroxide, potassium hydroxide,    lithium hydroxide, etc.), a hydroxide of an alkali earth metal    (barium hydroxide or calcium hydroxide, etc.), a carbonate (sodium    carbonate or potassium carbonate, etc.), an aqueous solution    thereof, or a mixture thereof at a temperature of 0 to 40° C.-   (2) The deprotection reaction under acidic conditions is carried    out, for example, in an organic solvent (methylene chloride,    chloroform, dioxane, ethyl acetate, anisole, etc.) or in the absence    of an organic solvent, in an organic acid (acetic acid,    trifluoroacetic acid, methanesulfonic acid, etc.), an inorganic acid    (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof    (hydrogen bromide/acetic acid, etc.) at a temperature of 0 to 100°    C.-   (3) The deprotection reaction by hydrogenolysis is carried out, for    example, in a solvent (ethers (tetrahydrofuran, dioxane,    dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol,    etc.), benzenes (benzene, toluene, etc.), ketones (acetone,    methylethylketone, etc.), nitrites (acetonitrile, etc.), amides    (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a    mixed solvent of at least two of these) in the presence of a    catalyst (palladium-carbon, palladium black, palladium hydroxide,    platinum oxide, Raney nickel, etc.) under the hydrogen atmosphere at    normal pressure or under pressurization, or in the presence of    ammonium formate at a temperature of 0 to 200° C.-   (4) The deprotection reaction of a silyl group is carried out, for    example, in a water-miscible organic solvent (tetrahydrofuran,    acetonitrile, etc.) using tetrabutylammonium fluoride at a    temperature of 0 to 40° C.

The protective group for hydroxyl includes methoxymethyl,2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl,benzyl and triphenylmethyl.

The protective group for amino includes benzyloxylcarbonyl,t-butoxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl.

The protective group for thiol includes benzyl, methoxybenzyl,acetoamidemethyl, triphenylmethyl and acetyl.

The protective group for carboxyl includes methyl, ethyl, t-butyl andbenzyl.

The protective group for hydroxyl, amino, thiol or carboxyl is notparticularly limited to the above-described groups, so long as it can beeasily and selectively left. For example, those described in T. W.Greene, Protective Groups in Organic Synthesis 3rd edition, Wiley, NewYork, 1999 can be used.

As is easily understood by those skilled in the art, an object compoundof the present invention can be produced easily by using a differentdeprotection reaction depending on usage.[2] The compound represented by formula (I-A) can also be produced bysubjecting a compound represented by formula (III):

(wherein all symbols have the same meanings as defined above) to acyclization reaction to thereby give a compound represented by formula(I-1), followed by deprotection reaction of a protective group, ifnecessary.

The above-described cyclization reaction is known and is carried out,for example, in an organic solvent (dichloromethane, diethyl ether,tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presenceof an azo compound (diethyl azodicarboxylate, diisopropylazodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine,1,1′-azobis(N,N-dimethylformamide), etc.) and a phosphine compound(triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) at atemperature of 0 to 60° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[3] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein E² represents an oxygen atom or a sulfuratom, i.e., a compound represented by formula (I-2):

(wherein E² represents an oxygen atom or a sulfur atom and other symbolshave the same meanings as defined above) can also be produced byreacting a compound represented by formula (IV):

(wherein all symbols have the same meanings as defined above) with acompound represented by formula (V):

(wherein G represents hydroxyl or a thiol and other symbols have thesame meanings as defined above) to thereby give a compound representedby formula (I-2′):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The reaction of the compound represented by formula (IV) with thecompound represented by formula (V) is known and carried out, forexample, in an organic solvent (dichloromethane, diethyl ether,tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presenceof an azo compound (diethyl azodicarboxylate, diisopropylazodicarboxylate, 1,1′-(azodicarbonyl) dipiperidine,1,1′-azobis(N,N-dimethylformamide), etc.) and a phosphine compound(triphenylphosphine, tributylphosphine, trimethylphosphinem, etc.) at atemperature of 0 to 60° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[4] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein G represents a carbon atom and only one R²is bound at the 3-position of piperidin-2-one, i.e., a compoundrepresented by formula (I-3):

(wherein all symbols have the same meanings as defined above) can bealso produced by reacting a compound among the compounds (I-1) producedby the above-described method, in which n represents O, i.e., a compoundrepresented by formula (I-1-4):

(wherein all symbols have the same meanings as defined above) with acompound represented by formula (VI):R²⁻¹—X  (VI)(wherein all symbols have the same meanings as defined above) to therebygive a compound represented by formula (I-4):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The reaction of the compound represented by formula (I-1-4) with thecompound represented by formula (VI) is known and can be carried out,for example, in an organic solvent (diethyl ether, tetrahydrofuran,etc.) in the presence of a base (lithium bis(trimethylsilyl)amide,potassium bis(trimethylsilyl)amide, lithium diisopropylamide, butyllithium, tert-butoxy potassium, sodium methoxide, sodium ethoxide,sodium hydride, potassium hydride, etc.) at a temperature of −80 to 20°C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[5] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein at least one of R¹ represents amino, i.e.,a compound represented by formula (I-5):

(wherein j represents 0 or an integer of 1, 2, 3, or 4 and other symbolshave the same meanings as defined above) can also be produced byreducing a compound among the compounds (I-1) produced by theabove-described method, in which at least one of R¹ represents nitro,i.e., a compound represented by formula (I-1-5):

(wherein all symbols have the same meanings as defined above) to therebygive a compound represented by formula (1-6):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The reduction reaction of nitro is known and carried out, for example,by a hydrogenation reaction and a reduction reaction using a metal.

The hydrogenation reaction is known and a deprotection reaction byhydrogenation is carried out, for example, in an inactive solvent[ethers (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether,etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g.,benzene, toluene, etc.), ketones (e.g., acetone, methylethylketone,etc.), nitrites (e.g., acetonitrile, etc.), amides (e.g.,dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixtureof at least two of them] in the presence of a hydrogenation catalyst(e.g., palladium-carbon, palladium black, palladium, palladiumhydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride,etc.) in the presence or in the absence of an inorganic acid (e.g.,hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid,tetrafluoroboric acid, etc.) or an organic acid (e.g., acetic acid,p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid,etc.) under the hydrogen atmosphere at normal pressure or underpressurization, or in the presence of ammonium formate at a temperatureof 0 to 200° C. When an acid is used, a salt thereof may be used.

The reduction reaction using a metal is known and is carried out, forexample, in a water-miscible solvent (ethanol, methanol, acetic acid,etc.) in the presence or in the absence of an aqueous hydrochloric acidsolution using a metal (zinc, iron, tin, tin chloride, iron chloride,etc.) at a temperature of 50 to 150° C.

Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein at least one of R³ represents amino can beproduced in the same manner.[6] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein at least one of R¹ represents —NR⁵R⁶, R⁵represents C1-4 alkyl or C1-4 alkyl substituted with 1 to 3 of Cyc1(wherein a carbon atom adjacent to a nitrogen atom is substituted withone Cyc1) and R⁶ represents a hydrogen atom, i.e., a compoundrepresented by formula (I-7):

(wherein R^(a) represents a hydrogen atom, C1-3 alkyl, Cyc1 or C1-3alkyl substituted with 1 to 3 of Cyc1 and other symbols have the samemeanings as defined above) can also be produced by subjecting thecompound represented by formula (I-6) produced in the above-describedmethod and a compound represented by formula (VII):R^(a-1)—CHO  (VII)(wherein R^(a-1) has the same meaning as R^(a), however, hydroxyl,amino, thiol or carboxyl contained in Cyc1 is protected when aprotection is necessary, and other symbols have the same meanings asdefined above) to a reductive amination reaction to thereby give acompound represented by formula (I-8):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The reductive amination reaction may be carried out after isolating animine generated from the compound represented by formula (I-6) and thecompound represented by formula (VII), or an imine is generated in areaction system and a reduction may be carried out (in one pot) withoutisolation.

The above-described imine generation reaction is known and is carriedout, for example, in an organic solvent (e.g., methanol, ethanol,methylene chloride, chloroform, dichloroethane, benzene, toluene, etc.)in the presence or in the absence of a dehydrating agent (e.g.,anhydrous magnesium sulfate, Molecular Sieve (proprietary name), etc.),in the presence or in the absence of an acid (e.g., hydrochloric acid,acetic acid, etc.) at a temperature of 20° C. to the reflux temperature.

The above-described reduction reaction of imine is known and is carriedout, for example, in an organic solvent (e.g., tetrahydrofuran, diethylether, dichloroethane, dichloromethane, dimethylformamide, acetic acid,methanol, ethanol, a mixture thereof, etc.) in the presence of a reducer(sodium triacetoxyborohydride, sodium cyanoborohydride, sodiumborohydride, zinc borohydride, diisobutyl aluminum hydride, etc.) at atemperature of 0 to 40° C., or in a solvent (ethers (tetrahydrofuran,dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol,ethanol, etc.), benzenes (benzene, toluene, etc.), ketones (acetone,methylethylketone, etc.), nitrites (acetonitrile, etc.), amides(dimethylformamide, etc.), water, ethyl acetate, acetic acid, a mixtureof at least two of them, etc.) in the presence of a catalyst(palladium-carbon, palladium black, palladium hydroxide, platinumdioxide, Raney nickel, etc.) under the hydrogen atmosphere at normalpressure or under pressurization at a temperature of 0 to 200° C.

The above-described reductive amination reaction is known and is carriedout, for example, in an organic solvent (e.g., dichloroethane,dichloromethane, dimethylformamide, acetic acid or a mixture thereof) inthe presence of a reducer (sodium triacetoxyborohydride, sodiumcyanoborohydride or sodium borohydride) at a temperature of 0 to 40° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[7] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein at least one of R¹ represents —NR⁷COR⁸ andR⁷ represents hydrogen, i.e., a compound represented by formula (I-9):

(wherein all symbols have the same meanings as defined above) can alsobe produced by subjecting the compound represented by formula (I-6)produced by the above-described method and a compound represented byformula (VIII):

(wherein R⁸⁻¹ has the same meaning as R⁸, however, hydroxyl, amino,thiol or a carboxyl contained in the group represented by R⁸⁻¹ isprotected when a protection is necessary) to an amidation reaction tothereby give a compound represented by formula (I-10):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The above-described amidation reaction is known and it includes, forexample,

-   (1) a method using an acid halide,-   (2) a method using a mixed acid anhydride-   (3) a method using a condensing agent and the like.

These methods are described specifically as follows.

-   (1) The method using an acid halide is carried out, for example, by    reacting a carboxylic acid in an organic solvent (chloroform,    methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without    a solvent, with an acid halogenation agent (oxalyl chloride, thionyl    chloride, etc.) at a temperature of −20° C. to the reflux    temperature, and by reacting the obtained acid halide in the    presence of a tertiary amine (pyridine, triethylamine,    dimethylaniline, dimethylaminopyridine, etc.) in an amine and an    inactive organic solvent (chloroform, methylene chloride, diethyl    ether, tetrahydrofuran, etc.) at a temperature of 0 to 40° C.    Further, this method can also be carried out in an organic solvent    (dioxane, tetrahydrofuran, etc.) using an aqueous alkaline solution    (aqueous sodium bicarbonate solution, sodium hydroxide solution,    etc.) with an acid halide at a temperature of 0 to 40° C.-   (2) The method using a mixed acid anhydride is carried out, for    example, by reacting a carboxylic acid in an organic solvent    (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,    etc.) or without a solvent in the presence of a tertiary amine    (pyridine, triethylamine, dimethylaniline, dimetylaminopyridine,    etc.) with an acid halide (pivaloyl chloride, tosyl chloride, mesyl    chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl    chloroformate, etc.) at a temperature of 0 to 40° C., and reacting    the obtained mixed acid anhydride in an organic solvent (chloroform,    methylene chloride, diethyl ether, tetrahydrofuran, etc.) with an    amine at a temperature of 0 to 40° C.-   (3) The method using a condensing agent is carried out, for example,    by reacting a carboxylic acid and an amine in an organic solvent    (chloroform, methylene chloride, dimethylformamide, diethyl ether,    tetrahydrofuran, etc.) or without a solvent in the presence or in    the absence of a tertiary amine (pyridine, triethylamine,    dimethylaniline, dimetylaminopyridine, etc.) using a condensing    agent (1,3-dicyclohexylcarbodiimide (DCC),    1-ethyl-3-[3-(demethylamino)propyl]carbodiimide (EDC),    1-1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine,    1-propyl-phosphonic acid cyclic anhydride (PPA), etc.) with or    without 1-hydroxylbenztriazole (HOBt) at a temperature of 0 to 40°    C.

These (1), (2) and (3) reactions are preferably carried out under theinactive gas (argon, nitrogen, etc.) atmosphere and anhydrousconditions.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[8] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein at least one of R¹ represents —NR⁷COR⁸ andR⁷ does not represent a hydrogen atom, i.e., a compound represented byformula (I-11):

(wherein R⁷⁻¹¹ has the same meaning as R⁷, however, R⁷⁻¹¹ does notrepresent a hydrogen atom and other symbols have the same meanings asdefined above) can also be produced by reacting the compound representedby formula (I-10) and a compound represented by formula (IX):R⁷⁻¹¹⁻¹—X  (IX)(wherein R⁷⁻¹¹⁻¹ has the same meaning as R⁷⁻¹¹, however, hydroxyl, anamino, a thiol or a carboxyl contained in a group represented by R⁷⁻¹¹⁻¹is protected when a protection is necessary) to thereby give a compoundrepresented by formula (I-12):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The reaction of the compound represented by formula (I-11) with thecompound represented by formula (IX) is known and can be carried out,for example, in an organic solvent (diethyl ether, tetrahydrofuran,N,N-dimethylformamide, etc.) in the presence of a base (sodium hydride,potassium hydride, etc.) at a temperature of −20 to 60° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[9] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein E² represents —NR²¹, i.e., a compoundrepresented by formula (I-13):

(wherein all symbols have the same meanings as defined above) can alsobe produced by subjecting a compound represented by formula (II-13):

(wherein all symbols have the same meanings as defined above), and acompound represented by formula (III-13):

(wherein all symbols have the same meanings as defined above) to areductive amination reaction to thereby give a compound represented byformula (I-13′):

(wherein R²¹⁻¹ has the same meaning as R²¹, however, hydroxyl, amino,thiol or carboxyl contained in the group represented by R²¹ is protectedwhen a protection is necessary, and other symbols have the same meaningsas defined above), followed by deprotection reaction of a protectivegroup, if necessary.

The reductive amination reaction and the deprotection reaction of aprotective group can be carried out in the same manner as describedabove.[10] Among the compounds represented by formula (I-A) of the presentinvention, a compound wherein E² represents —NR⁷⁹SO₂—i.e., a compoundrepresented by formula (I-14):

(wherein all symbols have the same meanings as defined above) can alsobe produced by subjecting a compound represented by formula (II-13):

(wherein all symbols have the same meanings as defined above), and acompound represented by formula (III-13):

(wherein all symbols have the same meanings as defined above) to asulfonamidation reaction to thereby give a compound represented byformula (I-14′):

(wherein R⁷⁹⁻¹ has the same meaning as R²¹, however, hydroxyl, amino,thiol or carboxyl contained in the group represented by R⁷⁹ is protectedwhen a protection is necessary, and other symbols have the same meaningsas defined above), followed by deprotection reaction of a protectivegroup, if necessary.

The sulfonamidation reaction is known and is carried out, for example,by reacting a sulfonyl halide with an amine in the presence of a base(diisopropylethylamine, pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, etc.) in an organic solvent (chloroform,dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, etc.)at a temperature of 0 to 40° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[11] The compound represented by formula (I-A) of the present inventioncan also be produced by reacting a compound represented by formula(II-15-1):

(wherein X represents a leaving group (e.g., chlorine atom, bromineatom, iodine atom, tosyl, mesyl) and other symbols have the samemeanings as defined above) or a compound represented by formula(II-15-2):

(wherein X represents a leaving group (e.g., chlorine atom, bromineatom, iodine atom, tosyl, mesyl) and other symbols have the samemeanings as defined above) with a compound represented by formula(III-15):

(wherein all symbols have the same meanings as defined above), followedby cyclization to thereby give a compound represented by formula(I-15′):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

This reaction is known and carried out in an organic solvent (benzene,toluene, xylene, etc.) with an amine at a temperature of 20 to 150° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.[B] Among the compounds represented by formula (I) of the presentinvention a compound wherein

represents a double bond, i.e., a compound represented by formula (I-B):

(wherein E^(B) represents C1-3 alkylene and other symbols have the samemeanings as defined above) can be produced by subjecting a compoundproduced by the above-described method, i.e., a compound represented byformula (I-16):

(wherein X represents a leaving group (e.g., chlorine atom, bromineatom, iodine atom, tosyl, mesyl) and other symbols have the samemeanings as defined above) to an elimination reaction to thereby give acompound represented by formula (I-B′):

(wherein all symbols have the same meanings as defined above), followedby deprotection reaction of a protective group, if necessary.

The elimination reaction is known and carried out by a reaction in anorganic solvent (methanol, ethanol, etc.) with a base (sodium hydroxide,potassium hydroxide or an aqueous solution thereof, etc.) at atemperature of 0 to 40° C.

The deprotection reaction of a protective group can be carried out inthe same manner as described above.

The compounds represented by formulae (II) to (IX) are either known perse or can be produced easily by a known method.

For example, the compounds represented by formulae (II) and (III) can beproduced by the method described in the following reaction process 1.

In the reaction process, Et represents ethyl and other symbols have thesame meanings as defined above.

Each reaction in the above reaction process is carried out by a knownmethod. In the reaction process, the compounds represented by formulae(X), (XI) and (XIII) used as the starting materials are either known orcan be produced easily by a known method.

In each reaction in this description, a reaction product can be purifiedby a general purification method, for example, distillation under normalor reduced pressure, high speed liquid chromatography using silica gelor magnesium silicate, thin layer chromatography or columnchromatography, washing, re-crystallization or the like. Purificationmay be carried out at each reaction or after completion of severalreactions.

Other staring materials and each reagent of the present invention areeither known per se or can be produced easily by a known method.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a photograph showing the suppression of ATF-2 phosphorylationby p38αMAP kinase by the compound of the present invention produced inExample 1 (1).

PHARMACOLOGICAL ACTIVITY OF COMPOUND OF THE PRESENT INVENTION

It was demonstrated that the compound of the present invention hasp38αMAP kinase inhibition activity by the following experiments.

(1) Study of p38αMAP Kinase Inhibitory Activity (1)

Using activation transcription factor 2 (activating transcription factor2; ATF-2, Cell Signaling Inc., #9224L) which is a substrate of p38αMAPkinase, the inhibitory effect of the compound of the present inventionon the ATF-2 phosphorylation by recombinant human p38αMAP kinase(Upstate Biotechnology Inc., #14-251) was studied by theWestern-blotting method using the anti-phosphorylated ATF-2 antibody(Cell Signaling Inc., #9221L). In other words, 10 μL of a solution ofthe compound of the present invention at a known concentration was addedto 10 μL of the kinase buffer (Cell Signaling Inc., #9802) containingrecombinant human p38αMAP kinase (100 ng/tube) and pre-incubated for 10minutes at 30° C. Then, 20 μL of adenosine triphosphate (ATP)/ATF-2mixture was added and after the incubation of 30 minutes at 30° C., 20μL of SDS buffer (187.5 mM Tris/6% SDS/30% glycerol/150 mM DTT/0.03%bromophenol blue) was added to stop the enzyme reaction. After heatingat 100° C. for 5 minutes, mixing and centrifugation were conducted.After re-mixing, 20 μL of the sample was subjected to an electrophoresison SDS-PAGE gel (10-20%, Daiichi Pure Chemicals Co., Ltd.). After theelectrophoresis, blotting was conducted on PVDF membrane (Sequi-Blot(proprietary name), 0.2 μm, BIO-RAD) by a conventional method. Afterthat, the PVDF membrane was treated with Block Ace (Snow Brand MilkProduct Co., Ltd.) (at room temperature, for 1 hour). After reacted withthe anti-phosphorylated ATF-2 antibody for 1.5 hours, it was washed withTBS-T solution (0.02 M Tris/0.137 M NaCl/0.05% Tween 20, pH 7.6).Furthermore, the reaction with a secondary antibody (anti-rabbit IgG,horseradish peroxide linked whole antibody, Amersham LIFE SCIENCE) wasconducted for 1 hour. After washing with TBS-T solution, phosphorylatedATF-2 was detected using Western blotting detection reagent (AmershamPharmacia Biotech).

FIG. 1 shows the result using the compound of the present inventionproduced in Example 1 (1).

As is shown in FIG. 1, the compound of the present invention produced inExample 1 (1) inhibited the ATF-2 phosphorylation by p38αMAP kinase atthe concentration of 0.3 μM or more. Further, other compounds of thepresent invention inhibited the ATF-2 phosphorylation by p38αMAP kinaseat the concentration of 1 μM or more.

(2) Study of p38αMAP Kinase Inhibitory Activity (2)

Using activation transcription factor 2 (hereinafter abbreviated asATF-2) which is a substrate of p38αMAP kinase, the inhibition effect ofthe compound of the present invention on the ATF-2 phosphorylation byrecombinant human p38αMAP kinase was examined.

Experimental Method:

A kinase buffer (25 mM Tris-HCl (pH 7.5), 5 mM β-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂) containing recombinant humanp38αMAP kinase (Upstate Biotechnology #14-251) (5 μL) was added to a384-well plate for fluorescence measurement (6.25 μg protein/well).Furthermore, a kinase solution containing the compound of the presentinvention (5 μL) was added and incubated at room temperature for 20minutes. Separately, 5 μL of a substrate mixture prepared with thekinase buffer (biotinylated ATF-2 (5 μg/mL) (Upstate Biotechnology,#14-432), adenosine triphosphate (90 μmol/L) (Sigma #FL-AAS) andanti-phosphorylated ATF-2 antibody (20-fold dilution) (Cell SignalingTechnology, #9221L) were added and an enzyme reaction was carried out at30° C. for 30 minutes. After completion of the reaction, the enzymereaction was terminated by adding 5 μL of Hepes buffer containing 0.25%BSA and 100 mM EDTA. The amount of complex of phosphorylated ATF2 andanti-phosphorylated ATF2 generated by this reaction was measured usingAlpha Screen™ Rabbit Detection kit (Packard #6760607).

The enzyme inhibitory activity against p38MAP kinase, which is theeffect of the compound of the present invention, was calculated as aninhibition rate (%) by the following formula.Inhibition rate (%)={(A _(C) −A _(X))/(Ac−A _(B))}×100

-   -   A_(B): Measured value without enzyme addition    -   A_(C): Measured value with enzyme addition in the absence of the        compound    -   A_(X): Measured value with enzyme addition in the presence of        the compound

As a result, the compound of the present invention showed the IC₅₀ of 10μM or less. For example, the IC₅₀ of the compound described in Example 1(1) was 42.9 nM.

(3) Effect on Mouse Cytokine Production

The compound of the present invention suspended in 0.5% methyl cellulose(MC) was orally administered to a male Balb/c mouse (Charles RiverJapan, Inc.), and after 0.5 hour, lipopolysaccharide (LPS, 055:B5,Difco) was intraperitoneally administered at the dose of 1 mg/kg (5animals/group). MC (0.5%) was orally administered to a control group (5animals). Ninety minutes after the LPS treatment, heparinized bloodcollection was performed via the abdominal main vain under anesthesiawith ether and blood plasma was obtained by centrifugation (12,000 rpm,3 minutes, 4° C.). The obtained blood plasma sample was stored at −80°C. until it was used. TNF-α and IL-6 in the blood plasma were measuredusing ELISA kits from R&D Inc. (#MTA00) and Endogen Inc. (#EM2IL6),respectively.

From the result of the above measurement, the compound of the presentinvention was found to significantly suppress cytokine production.

(4) Inhibition Activity Against TNF-α Production Using Human Cell Line

Using THP-1, which is a human monocyte cell line, the inhibition effectof the compound of the present invention on the TNF-α production inducedby lipopolyliposaccharide (LPS) stimulation was studied.

Experimental Method:

Each 50 μL of lipopolyliposaccharide (LPS; Difco #3120-25-0) prepared atthe concentration of 40 ng/mL using RPMI-1640 medium containing 10%fetal calf serum (hereinafter abbreviated as RPMI-1640) and RPMI-1640containing the compound of the present invention was added to a 96-wellplate for tissue culture. A portion of 100 μL of the cell suspensionsolution of THP-1 (Dainippon Pharmaceutical Co., Ltd, #06-202) preparedat the cell density of 2×10⁶ cells/mL using RPMI-1640 was added andcultured for 90 minutes at 37° C. in an incubator (5% CO₂, 95% Air).After completion of the reaction, the culture medium supernatant wasrecovered and the amount of produced TNF-α was measured using an ELISAkit (Invitrogen, #850090192).

The inhibition activity against TNF-α production, which is the effect ofthe compound of the present invention, was calculated as an inhibitionrate (%) by the following formula.Inhibition rate (%)={(A _(C) −A _(X))/(A _(C) −A _(B))}×100

-   -   A_(B): Measured value without LPS induction    -   A_(C): Measured value with LPS induction in the absence of the        compound    -   A_(X): Measured value with LPS induction in the presence of the        compound

As a result, the compound of the present invention showed the IC₅₀ of 10μM or less. For example, the IC₅₀ of the compound described in Example 1(1) was 14.5 nM.

[Toxicity]

Toxicity of the compound represented by formula (I) of the presentinvention is sufficiently low, and it was confirmed to be safe enoughfor use as a pharmaceutical agent.

[Application for Pharmaceuticals]

The compound represented by formula (I) of the present inventionsuppresses p38MAP kinase activation, therefore it is expected to beuseful in the prevention and/or the treatment of various inflammatorydiseases, rheumatoid arthritis, osteoarthritis, arthritis, osteoporosis,autoimmune diseases, infectious diseases, sepsis, cachexia, cerebralinfarction, Alzheimer's disease, asthma, chronic pulmonary inflammatorydiseases, reperfusion injury, thrombosis, glomerulonephritis, diabetes,graft versus host rejection, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, multiple sclerosis, tumor growth andmetastasis, multiple myeloma, plasma cell leukemia, Castleman's disease,atrial myxoma, psoriasis, dermatitis, gout, adult respiratory distresssyndrome (ARDS), arteriosclerosis, post-percutaneous transluminalcoronary angioplasty restenosis and pancreatitis.

The compounds represented by formula (I) or the non-toxic salts thereofmay be administered in combination with other drugs for the purposeof 1) complement and/or enhancement of preventing and/or treatingeffect, 2) improvement of dynamics and absorption of the compound, andlowering of dose, and/or 3) alleviation of side effect of the compound.

The compounds represented by formula (I) may be administered incombination with other drugs as a composition in one drug productcomprising these components, or may be administered separately. Whenthey are administered independently, they may be administeredsimultaneously or with time lag. Administering with time lag includesthe method of administering the compounds represented by formula (I)before other drugs and vice versa; they may be administered in the sameroute or not.

The above combination drugs takes effect on whichever disease preventingand/or treatment effect of the compound of formula (I) is complementedand/or enhanced.

The weight proportion of the compounds represented by formula (I) andthe other drugs is not specifically limited.

Arbitrary two or more of the other drugs may be administered incombination.

Examples of the other drugs for compensating for and/or enhancing thepreventive and/or treatment effect of the compounds represented byformula (I) include not only those which have so far been found but alsothose which will be found on the basis of the aforementioned mechanism.

Other agents to complement and/or enhance a prevention and/or atreatment effect of the compound represented by formula (I) onrheumatoid arthritis, osteoarthritis, arthritis or the like include asteroidal agent, an elastase inhibitor, a cannabinoid-2 receptorstimulating agent, a prostaglandin, a prostaglandin synthase inhibitor,a phosphodiesterase inhibitor, a metalloproteinase inhibitor, anadhesion molecule inhibitor, an anti-TNF-α agent, an immunosuppressingagent, a disease modifying anti-rheumatic agent, a non-steroidalanti-inflammatory agent and the like.

Other agents to complement and/or enhance prevention and/or treatmenteffect of the compound represented by formula (I) on inflammatory boweldisease, Crohn's disease or ulcerative colitis include a steroidalagent, an elastase inhibitor, a cannabinoid-2 receptor stimulatingagent, a prostaglandin, a prostaglandin synthase inhibitor, aphosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesionmolecule inhibitor, an anti-TNF-α agent, an immunosuppressing agent, aleukotoriene receptor antagonist, an anti-choline agent, a5-lipoxygenase inhibitor, a nitric monooxide synthase inhibitor, aninterleukin 8 antagonist, a poly(ADP)-ribose polymerase inhibitor, amitochondrial benzodiazepine receptor agonist, an anti-oxidation agent,a topical anesthetic, an agent for digestive tract ulcer, a defensefactor enhancing agent, mesalazine, salazosulfapyridine and the like.

Other agents to complement and/or enhance prevention and/or treatmenteffect of the compound represented by formula (I) on asthma, chronicpulmonary inflammatory diseases or adult respiratory distress syndrome(ARDS) include a steroidal agent, an elastase inhibitor, a cannabinoid-2receptor stimulating agent, a prostaglandin, a prostaglandin synthaseinhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor,an adhesion molecule inhibitor, a leukotoriene receptor antagonist, ananti-choline agent, a thromboxane A2 receptor antagonist, a thromboxanesynthase inhibitor, a β2 adrenaline receptor stimulating agent, axanthine derivative, an expectorant agent, an antibiotic, ananti-histamine agent, a cytokine inhibitor, a forskolin agent, amediator release inhibitor and the like.

The steroidal agent includes clobetasol propionate, diflorasonediacetate, fluocinonide, mometasone furancarboxylate, betamethasonedipropionate, betamethasone butyrate propionate, betamethasone valerate,difluprednate, diflucortolone valerate, amcinonide, halcinonide,dexamethasone, dexamethasone propionate, dexamethasone valerate,dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone butyrate propionate, deprodone propionate, prednisolonevalerate acetate, fluocinolone acetonide, beclometasone dipropionate,triamcinolone acetonide, flumetasone pivalate, alclometasonedipropionate, clobetasone butyrate, prednisolone, fludroxycortide,cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, fludrocortisone acetate, prednisoloneacetate, prednisolone sodium succinate, prednisolone butylacetate,prednisolone sodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, betamethasone,fluticasone propionate, budesonide, flunisolide, ST-126P, ciclesonide,dexamethasone palmitate, mometasone furancarbonate, prasteronesulfonate, deflazacort, methylprednisolone suleputanate,methylprednisolone sodium succinate and the like.

The elastase inhibitor includes ONO-5046, ONO-6818, MR-889, PBI-1101,EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, DMP-777, L-659286,L-658758, L-680833, L-683845, AE-3763 and the like.

The prostaglandin (hereinafter referred to as “PG”) includes a PGreceptor agonist, a PG receptor antagonist and the like.

The PG receptor includes a PGE receptor (EP1, EP2, EP3, EP4), a PGDreceptor (DP, CRTH2), a PGF receptor (FP) a PGI receptor (IP), a TXreceptor (TP) and the like.

The prostaglandin synthase inhibitor includes salazosulfapyridine,mesalazine, osalazine, 4-amino salicylic acid, JTE-522, auranofin,carprofen, difenpiramide, flunoxaprofen, flurbiprofen, indometacin,ketoprofen, lomoxicam, loxoprofen, meloxicam, oxaprozin, parsalmide,piproxen, piroxicam, piroxicam betadex, piroxicam cinnamate, tropineindometacinate, zaltoprofen, pranoprofen and the like.

The phosphodiesterase inhibitor includes a PDE 4 inhibitor such asrolipram, cilomilast (Proprietary name: Ariflo), Bay19-8004, NIK-616,roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633),SCH-351591, YM-976, V-11294A, PD-168787, D-4396 or IC-485, and a PDE 5inhibitor such as sildenafil.

The adhesion molecule inhibitor includes an antagonist such as α4integrin, and the like.

The anti-TNF-α agent includes an antibody against TNF-α, a soluble TNF-αreceptor, an antibody against a TNF-α receptor and the like, and theanti-TNF-α agent includes infliximab, etanercept and the like.

The immunosuppressing agent includes methotrexate, cyclosporin,ascomycin, leflunomide, bucillamine, salazosulfapyridine, azathioprine,tacrolimus, cyclophosphamide and the like.

The disease modifying anti-rheumatic agent includes aurothioglucose,sodium aurothiomalate, auranofin, actarit, D-penicillamine preparation,lobenzarit disodium, bucillamine, hydroxychloroquine,salazosulfapyridine and the like.

The non-steroidal anti-inflammatory agent includes sasapyrine, sodiumsalicylic acid, aspirin, aspirin dialuminate combinations, diflunisal,indomethacin, suprofen, ufenamate, dimethyl-isopropyl-azulene,bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen,napumetone, proglumetacin, indomethacin farnesil, acemetacin,proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen,ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil,ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen,loxoprofen sodium, aminoprofen, zaltoprofen, mefenamic acid, aluminummefenamaic acid, tolfenamic acid, floctafenine, ketophenylbutazone,oxyphenbutazone, pyroxicam, tenoxicam, ampiroxicam, Napageln ointment,epirizole, tiaramide hydrochloride, tinoridine hydrochloride,emorfazone, sulpyrine, migrenin, Saridon, Sedes G, Amipylo N, sorbone,pilin derivatives for cough and cold preparations, acetaminophen,phenacetin, dimetotiazine mesilate, simetride combinations, non-pilinderivatives for cough and cold preparations and the like.

The leukotoriene receptor antagonist includes pranlukast hydrate,montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158,L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284,ONO-4057 and the like.

The anti-choline agent includes ipratropium bromide, oxitropium bromide,flutropium bromide, cimetropium bromide, temiverine, thiotropiumbromide, revatropate (UK-112166) and the like.

The topical anesthetic includes cocaine hydrochloride, procainehydrochloride, lidocaine, dibucaine hydrochloride, tetracainehydrochloride and the like.

The defense factor enhancing agent includes sucralfate, aldioxa,teprenone, cetraxate hydrochloride, ornoprostil and the like.

The thromboxane A2 receptor antagonist includes seratrodast, ramatroban,domitroban calcium hydrate, KT-2-962 and the like.

The thromboxane synthase inhibitor includes ozagrel hydrochloride,imitrodast sodium and the like.

The β2 adrenaline receptor stimulating agent includes fenoterolhydrobromide, salbutamol sulfate, terbutaline sulfate, formoterolfumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenalinesulfate, chlorprenaline sulfate, epinephrine, trimetoquinolhydrochloride, hexoprenalinemesyl sulfate, procaterol hydrochloride,tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride,clenbuterol hydrochloride, mabuterol hydrochloride, ritodrinehydrochloride, bambuterol, dopexamine hydrochloride, meruadrinetartrate, AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211,AR-C89855, S-1319 and the like.

The xanthine derivative includes aminophylline, theophylline,doxofylline, sipamphylline, diprophylline and the like.

The expectorant agent includes foeniculated ammonia spirit, sodiumhydrogen carbonate, bromhexine hydrochloride, carbocysteine, ambroxolhydrochloride, ambroxol hydrochloride sustained preparation,methylcysteine hydrochloride, acetylcysteine, ethyl L-cysteinehydrochloride, tyloxapol and the like.

The antibiotic includes sodium cefuroxime, meropenem trihydrate,netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367,tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetamet pivoxilhydrochloride and the like. As the antibiotic for an inhalant, forexample, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicinsulfate, cefetamet pivoxil hydrochloride and the like.

The anti-histamine agent includes ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine difumarate,epinastine hydrochloride, astemizole, ebastine, cetirizinehydrochloride, bepotastine, fexofenadine, loratadine, desloratadine,olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasonefuroate, mizolastine, BP-294, andolast, auranofin, acrivastine and thelike.

The cytokine inhibitor includes suplatast tosylate (proprietary name:IPD) and the like.

The mediator release inhibitor includes tranilast, sodium cromoglicate,amlexanox, repirinast, ibudilast, dazanolast, pemirolast potassium andthe like.

In order to use the compounds of the present invention represented byformula (I) or the non-toxic salts thereof, these compounds are normallyadministered to the entire or local part of human body orally orparenterally.

The dose of these compounds depends on the age, weight and symptom ofthe patient, the remedial value, the administration method, thetreatment time, etc. In practice, however, these compounds areadministered orally once or several times per day each in an amount offrom 1 μg to 100 mg per adult, parenterally once or several times perday each in an amount of from 0.1 μg to 10 mg per adult or continuouslyadministered into vein for 1 hour to 24 hours per day.

It goes without saying that the dose of these compounds may be less thanthe aforementioned value or may need to exceed the aforementioned rangebecause the dose varies under various conditions as mentioned above.

The compound of the present invention may be administered in thecomposition of, for example, solid compositions, liquid compositions orother compositions each for oral administration, or injections,liniments or suppositories, each for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, powders and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more of the active substance(s) maybe used in combination with at least one diluting agent such as lactose,mannitol, mannnit, glucose, hydroxypropylcellulose, microcrystallitecellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate,etc.

Solid compositions may comprise other additives by the law of the art,for example, lubricants (e.g. magnesium stearate etc.), disintegrants(e.g. cellulose calcium glycolate etc.), solubilizing agent (e.g.glutamic acid, aspartic acid, etc.), etc. in addition of diluting agent.If necessary, compressed tablets or pills may be coated with a gastricor enteric film (e.g. sucrose, gelatin, hydroxypropyl cellulose,hydroxypropyl cellulose phthalate, etc.), or with two or more layers.Furthermore, capsules made of a substance which can be absorbed in thebody, for example, gelatin, are included.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, syrups, elixirs, etc. In such liquidcompositions, one or more of the active substance(s) may be solved,suspended or emulsified in generally used inert diluent(s) (e.g.purified water, ethanol, etc.). The compositions may comprise, inaddition to the inert diluent, humectants, suspending agents,emulsifying agent, sweetening agents, flavoring agents, aromatic agentsand preservatives.

The other compositions for oral administration include sprays whichcomprise one or more of the active substance(s) and may be prepared bymethods known per se. Sprays may comprise in addition to a generallyused diluent, a stabilizer such as sodium bisulfite and an isotonizationbuffer such as sodium chloride, sodium citrate or citric acid. Thepreparation process of sprays is described in detail in, for example,U.S. Pat. Nos. 2,868,691 and 3,095,355.

Injections for parenteral administration include sterile aqueous ornonaqueous solutions, suspensions and emulsions. Solvent(s) for aqueoussolutions or suspentions may include, for example, distilled water forinjection, physiological salt solution. Solvent(s) for nonaqueoussolutions or suspentions may include, for example, propylene glycol,polyethylene glycol, vegetable oil (e.g. olive oil etc.), alcohol (e.g.ethanol etc.), POLYSORBATE80 (registered trade mark), etc.

Moreover, these injections may comprise some additives, such aspresertives, humectants, emulsifying agents, dispersing agents,stabilizing agents, solution adjuvants (e.g. glutamic acid, asparticacid, etc.). They may be sterilized by filtering through bacteriaremoval filter, blending of bactericidal substance, or irradiation. Theymay also be manufactured in the form of sterile solid forms which may bedissolved in sterile water or some other sterile diluent(s) forinjection immediately before use.

The other compositions for parenteral administration include liquidcompositions for external use, ointments, embrocations, suppositoriesfor rectal administration and pessaries for vaginal administration, etc.which comprise one or more of the active substance(s) and may beprepared by methods known per se.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on ReferenceExamples and Examples, however, the present invention is not limitedthereto.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC. The solvents in the parentheses in NMR show thesolvents for measurement.

REFERENCE EXAMPLE 1

ethyl 4-[N-(2,6-dichlorophenyl)carbamoyl]butanoate

Under an atmosphere of argon, to a solution of 2,6-dichloroaniline (5.96g) in N,N-dimethylformamide (50 ml) was added ethyl glutaryl chloride(9.87 g) in ice bath and the mixture was stirred at room temperature for5 hours. The reaction mixture was poured in water and extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium hydrogen carbonate solution, water and brine sequentially, anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe obtained residue was washed with isopropyl ether to give the titlecompound (7.67 g) having the following physical data.

TLC:Rf 0.41 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.37 (d, J=7.8 Hz, 2H), 7.23-7.05 (m, 2H), 4.15 (q, J=7.2Hz, 2H), 2.60-2.42 (m, 4H), 2.18-2.00 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 2

ethyl 4-[N-(2,6-dichlorophenyl)carbamoyl]-2-benzylbutanoate

Under an atmosphere of argon, a solution of the compound prepared inReference Example 1 (909 mg) in anhydrous tetrahydrofuran (20 ml) wascooled to −78° C., and thereto was dropped lithium diisopropylamide(1.5M solution in cyclohexane, 4.4 ml). The mixture was stirred for 30minutes and thereto was added benzyl bromide (0.39 ml). The mixture wasstirred at −60° C. for 1 hour. A saturated aqueous ammonium chloridesolution was added to the reaction mixture, which was extracted withethyl acetate. The organic layer was washed with water and brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe obtained residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4→3:7) to give the title compound (188 mg)having the following physical data.

TLC:Rf 0.53 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.30-7.13 (m, 6H), 7.07 (s, 1H),4.10 (q, J=7.2 Hz, 2H), 3.04-2.77 (m, 3H), 2.60-2.30 (m, 2H), 2.11-1.97(m, 2H), 1.17 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 3

4-[N-(2,6-dichlorophenyl)carbamoyl]-2-benzylbutanol

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 2 (180 mg) in anhydrous tetrahydrofuran (5 ml) wasadded lithium borohydride (170 mg) in ice bath and the mixture wasstirred at room temperature for 48 hours. The reaction mixture waspoured in iced water and thereto was added 1N hydrochloric acid. Thereaction mixture was extracted with ethyl acetate, washed with asaturated aqueous sodium hydrogen carbonate solution, water and brinesequentially, and dried over anhydrous magnesium sulfate. The solventwas evaporated and the obtained residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=3:2) to give thetitle compound (117 mg) having the following physical data.

TLC:Rf 0.17 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.34-7.15 (m, 6H), 7.10 (s, 1H),3.64 (m, 1H), 3.57 (m, 1H), 2.78-2.40 (m, 4H), 2.17 (br, 1H), 2.01-1.75(m, 3H).

REFERENCE EXAMPLE 4

4-[N-(2,6-dichlorophenyl)carbamoyl]-2-benzylbuthylbromide

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 3 (115 mg) in methylene chloride (5 ml) were addedtriphenylphosphine (155 mg) and carbon tetrabromide (247 mg) and themixture was stirred at room temperature for 1.5 hours. Ethyl acetate wasadded to the reaction mixture, which was washed with a saturated aqueoussodium hydrogen carbonate solution, water and brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated and the obtainedresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:4) to give the title compound (112 mg) having thefollowing physical data.

TLC:Rf 0.61 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.37 (d, J=7.8 Hz, 2H), 7.37-7.14 (m, 6H), 6.91 (s, 1H),3.48 (m, 1H), 3.38 (m, 1H), 2.81-2.62 (m, 2H), 2.60-2.40 (m, 2H), 2.12(m, 1H), 2.00-1.87 (m, 2H).

EXAMPLE 1

1-(2,6-dichlorophenyl)-5-benzylpiperidin-2-one

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 4 (110 mg) in anhydrous tetrahydrofuran (5 ml) wasadded potassium tert-butoxide (33 mg) in ice bath and the mixture wasstirred at 0° C. for 15 minutes. 1N hydrochloric acid was added to thereaction mixture, which was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium hydrogen carbonatesolution, water and brine sequentially, and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the obtained residuewas purified by column chromatography on silica gel (ethylacetate:hexane=3:7) to give the compound of the present invention (87mg) having the following physical data.

TLC:Rf 0.47 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.40-7.16 (m, 8H), 3.39-3.29 (m, 2H), 2.77-2.62 (m, 3H),2.58-2.30 (m, 2H), 2.01 (m, 1H), 1.72 (m, 1H).

EXAMPLES 1(1)˜1(12)

By the same procedure as described in Reference Example 2→ReferenceExample 3→Reference Example 4→Example 1 using the corresponding halideinstead of benzybromide, the following compounds of the presentinvention were obtained.

EXAMPLE 1(1)

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.34 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.42-7.34 (m, 2H), 7.24-7.08 (m, 2H), 6.87-6.77 (m, 2H),3.36 (d, J=8.1 Hz, 2H), 2.77-2.62 (m, 3H), 2.60-2.29 (m, 2H), 1.99 (m,1H), 1.73 (m, 1H).

EXAMPLE 1(2)

1-(2,6-dichlorophenyl)-5-(2-naphthylmethyl)piperidin-2-one

TLC:Rf 0.39 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.83-7.75 (m, 3H), 7.63 (s, 1H), 7.50-7.40 (m, 2H),7.39-7.30 (m, 3H), 7.18 (t, J=8.1 Hz, 1H), 3.42-3.30 (m, 2H), 2.97-2.82(m, 2H), 2.70 (ddd, J=18.0, 6.0, 3.6 Hz, 1H), 2.61-2.42 (m, 2H), 2.02(m, 1H), 1.78 (m, 1H).

EXAMPLE 1(3)

1-(2,6-dichlorophenyl)-5-(2,4-dimethylbenzyl)piperidin-2-one

TLC:Rf 0.42 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.34 (m, 2H), 7.20 (t, J=8.1 Hz, 1H), 7.03-6.91 (m,3H), 3.43-3.30 (m, 2H), 2.74-2.58 (m, 3H), 2.49 (m, 1H), 2.40-2.23 (m,7H), 2.01 (m, 1H), 1.72 (m, 1H).

EXAMPLE 1(4)

1-(2,6-dichlorophenyl)-5-(4-trifluoromethoxybenzyl)piperidin-2-one

TLC:Rf 0.20 (ethyl acetate:hexane=3:7);

NMR (CDCl₃):d 7.42-7.36 (m, 2H), 7.25-7.12 (m, 5H), 3.41-3.29 (m, 2H),2.80-2.63 (m, 3H), 2.52 (ddd, J=17.4, 10.8, 6.3 Hz, 1H), 2.38 (m, 1H),2.01 (m, 1H), 1.72 (m, 1H).

EXAMPLE 1(5)

1-(2,6-dichlorophenyl)-5-(4-trifluoromethylbenzyl)piperidin-2-one

TLC:Rf 0.27 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.57 (d, J=8.1 Hz, 2H), 7.41-7.36 (m, 2H), 7.32 (d, J=8.1Hz, 2H), 7.21 (m, 1H), 3.36 (d, J=7.8 Hz, 2H), 2.79 (d, J=7.2 Hz, 2H),2.69 (ddd, J=17.7, 5.7, 3.6 Hz, 1H), 2.60-2.32 (m, 2H), 2.00 (m, 1H),1.72 (m, 1H).

EXAMPLE 1(6)

1-(2,6-dichlorophenyl)-5-(3,5-difluorobenzyl)piperidin-2-one

TLC:Rf 0.36 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.42-7.34 (m, 2H), 7.21 (m, 1H), 6.80-6.63 (m, 3H),3.41-3.28 (m, 2H), 2.75-2.62 (m, 3H), 2.54 (ddd, J=17.7, 11.1, 6.3 Hz,1H), 2.38 (m, 1H), 2.00 (m, 1H), 1.72 (m, 1H).

EXAMPLE 1(7)

1-(2,6-dichlorophenyl)-5-(2-chlorobenzyl)piperidin-2-one

TLC:Rf 0.38 (ethyl acetate:hexane=2:3); NMR (CDCl₃):d 7.42-7.34 (m, 3H),7.25-7.14 (m, 4H), 3.46-3.34 (m, 2H), 2.94-2.77 (m, 2H), 2.69 (ddd,J=17.7, 5.7, 3.3 Hz, 1H), 2.59-2.40 (m, 2H), 2.00 (m, 1H), 1.77 (m, 1H).

EXAMPLE 1(8)

1-(2,6-dichlorophenyl)-5-(4-fluorobenzyl)piperidin-2-one

TLC:Rf 0.29 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.34 (m, 2H), 7.23-7.09 (m, 3H), 7.04-6.95 (m, 2H),3.37-3.27 (m, 2H), 2.74-2.61 (m, 3H), 2.52 (ddd, J=17.7, 11.4, 6.3 Hz,1H), 2.37 (m, 1H), 2.00 (m, 1H), 1.69 (m, 1H).

EXAMPLE 1(9)

1-(2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one

TLC:Rf 0.36 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.34 (m, 2H), 7.25-7.15 (m, 3H), 7.14-6.99 (m, 2H),3.38 (d, J=8.1 Hz, 2H), 2.76 (d, J=6.9 Hz, 2H), 2.69 (ddd, J=18.3, 6.0,3.6 Hz, 1H), 2.60-2.34 (m, 2H), 2.00 (m, 1H), 1.74 (m, 1H).

EXAMPLE 1(10)

1-(2,6-dichlorophenyl)-5-(1-naphthylmethyl)piperidin-2-one

TLC:Rf 0.48 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 8.01 (d, J=8.1 Hz, 1H), 7.90-7.87 (m, 1H), 7.76 (d, J=8.1Hz, 1H), 7.58-7.48 (m, 2H), 7.43-7.32 (m, 4H), 7.20 (t, J=8.1 Hz, 1H),3.53-3.40 (m, 2H), 3.22 (dd, J=6.6 Hz, 12.8 Hz, 1H), 3.11 (dd, J=7.8 Hz,12.8 Hz, 1H), 2.73-2.42 (m, 3H), 2.08-1.97 (m, 1H), 1.88-1.74 (m, 1H).

EXAMPLE 1(11)

1-(2,6-dichlorophenyl)-5-(2-methoxybenzyl)piperidin-2-one

TLC:Rf 0.46 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.34 (m, 2H), 7.25-7.08 (m, 3H), 6.92-6.84 (m, 2H),3.83 (s, 3H), 3.35 (d, J=8.4 Hz, 2H), 2.75-2.62 (m, 3H), 2.59-2.37 (m,2H), 1.98 (m, 1H), 1.70 (m, 1H).

EXAMPLE 1(12)

1-(2,6-dichlorophenyl)-5-(4-ethylbenzyl)piperidin-2-one

TLC:Rf 0.28 (ethyl acetate:hexane=3:7);

NMR (CDCl₃):d 7.40-7.35 (m, 2H), 7.19 (m, 1H), 7.13 (d, J=8.7 Hz, 2H),7.10 (d, J=8.7 Hz, 2H), 3.42-3.28 (m, 2H), 2.73-2.60 (m, 5H), 2.50 (m,1H), 2.38 (m, 1H), 2.00 (m, 1H), 1.70 (m, 1H), 1.23 (t, J=7.8 Hz, 3H).

EXAMPLE 2

1-(2,6-dichlorophenyl)-5-benzylpiperidin-2-one

Under an atmosphere of argon, a solution of the compound prepared inReference Example 3 (3.65 g) in tetrahydrofuran (50 ml) was cooled inice bath and thereto were added triphenylphosphine (4.92 g) and diethylazodicarboxylate (40% solution in toluene, 7.41 ml). The reactionmixture was stirred at 0° C. for 15 minutes. The reaction mixture wasconcentrated. The obtained residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=3:7) and washed with t-butyl methylether to give the compound of the present invention (1.89 g) having thefollowing physical data.

TLC:Rf 0.47 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.40-7.16 (m, 8H), 3.39-3.29 (m, 2H), 2.77-2.62 (m, 3H),2.58-2.30 (m, 2H), 2.01 (m, 1H), 1.72 (m, 1H).

EXAMPLE 3

1-(2-chlorophenyl)-5-benzylpiperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Example 1 using2-chloroaniline instead of 2,6-dichloroaniline, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.30 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.48-7.43, 7.33-7.16 (m, 9H), 3.49-3.39, 3.29-3.22 (m,2H), 2.73-2.27 (m, 5H), 2.07-1.95 (m, 1H), 1.79-1.65 (m, 1H).

EXAMPLE 4

1-(2,6-difluorophenyl)-5-benzylpiperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Example 1 using2,6-difluoroaniline instead of 2,6-dichloroaniline, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.53 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.33-7.17 (m, 6H), 6.99-6.91 (m, 2H), 3.46 (ddd, J=1.3 Hz,5.1 Hz, 11.4 Hz, 1H), 3.37 (dd, J=9.3 Hz, 11.4 Hz, 1H), 2.71 (d, J=7.5Hz, 2H), 2.68-2.62 (m, 1H), 2.58-2.46 (m, 1H), 2.44-2.30 (m, 1H),2.08-1.97 (m, 1H), 1.79-1.65 (m, 1H).

EXAMPLE 5

1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Example 1 using2,6-dimethylaniline instead of 2,6-dichloroaniline and2,4-difluorobenzylbromide instead of benzylbromide, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.31 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.17-7.05 (m, 4H), 6.87-6.75 (m, 2H), 3.29-3.18 (m, 2H),2.75-2.62 (m, 3H), 2.52 (ddd, J=18.3, 11.7, 6.6 Hz, 1H), 2.30 (m, 1H),2.21 (s, 3H), 2.12 (s, 3H), 2.00 (m, 1H), 1.66 (m, 1H).

Reference Example 5

2,6-dichloro-4-hydroxymethylaniline

Under an atmosphere of argon, to a solution of4-amino-3,5-dichlorobenzoic acid (2.5 g) in anhydrous tetrahydrofuran(100 ml) was added Borane-tetrahydrofuran complex (1.04 M solution intetrahydrofuran, 35 ml) in ice bath the mixture was stirred at roomtemperature for 1 hours. Methanol was added to the reaction mixture,which was concentrated. The residue was dissolved in ethyl acetate,washed with 1N hydrochloric acid, water, a saturated aqueous sodiumhydrogen carbonate solution, water and brine sequentially, and driedover anhydrous magnesium sulfate. The solvent was evaporated to give thetitle compound having the following physical data. The obtained compoundwas used in next reaction without purification.

TLC:Rf 0.32 (ethyl acetate:hexane=3:7);

NMR (CDCl₃):d 7.21 (s, 2H), 4.54 (d, J=4.5 Hz, 2H), 4.43 (s, 2H), 1.59(t, J=4.5 Hz, 1H).

REFERENCE EXAMPLE 6

2,6-dichloro-4-(1,1,1-triphenylmethoxymethyl)aniline

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 5 in N,N-dimethylformamide (20 ml) were addedtriethylamine (3.68 ml), trityl chloride (3.71 g) andN,N-dimethylaminopyridine (65 mg) in ice bath and the mixture wasstirred at room temperature for 12 hours. Ethyl acetate was added to thereaction mixture, which was washed with 1N hydrochloric acid, water, asaturated aqueous sodium hydrogen carbonate solution, water and brinesequentially, and dried over anhydrous magnesium sulfate. The solventwas evaporated and the obtained residue was washed with isopropyl etherto give the title compound (3.0 g) having the following physical data.

TLC:Rf 0.49 (ethyl acetate:hexane=1:9);

NMR (CDCl₃):d 7.50-7.43 (m, 6H), 7.37-7.20 (m, 9H), 7.16 (s, 2H), 4.40(s, 2H), 4.01 (s, 2H).

EXAMPLE 6

1-[2,6-dichloro-4-(1,1,1-triphenylmethoxymethyl)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Example 1 using thecompound prepared in Reference Example 6 instead of 2,6-dichloroanilineand 2,4-difluorobenzylbromide instead of benzylbromide, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.32 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.50-7.43 (m, 6H), 7.39-7.20 (m, 11H), 7.17 (m, 1H), 6.81(m, 2H), 4.14 (s, 2H), 3.34 (d, J=7.8 Hz, 2H), 2.76-2.62 (m, 3H), 2.52(ddd, J=17.7, 11.1, 6.3 Hz, 1H), 2.38 (m, 1H), 1.99 (m, 1H), 1.72 (m,1H).

EXAMPLE 7

1-(2,6-dichloro-4-hydroxymethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

The compound prepared in Example 6 (380 mg) was dissolved in a mixedsolvent of methylene chloride (1 ml) and water (0.1 ml). Trifluoroaceticacid (1 ml) was added thereto in ice bath and the mixture was stirred at0° C. for 1 hour. The reaction mixture was poured in an iced saturatedaqueous sodium hydrogen carbonate solution and extracted with ethylacetate. The organic layer was washed with water and brine and driedover anhydrous magnesium sulfate. The solvent was evaporated. Theobtained residue was purified by column chromatography on silica gel(ethyl acetate:hexane=3:2) and washed with isopropyl ether to give thetitle compound (162 mg) having the following physical data.

TLC:Rf 0.40 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.34 (s, 2H), 7.14 (m, 1H), 6.87-6.75 (m, 2H), 4.62-4.53(m, 2H), 3.34 (d, J=7.8 Hz, 2H), 2.77-2.61 (m, 3H), 2.59-2.28 (m, 3H),1.99 (m, 1H), 1.72 (m, 1H).

REFERENCE EXAMPLE 7

Ethyl 4-[N-(2,6-dichlorophenyl)carbamoyl]-2-hydroxybutanoate

Under an atmosphere of argon, a solution of the compound prepared inReference Example 1 (2.09 g) in anhydrous tetrahydrofuran (15 ml) wascooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0M solution intetrahydrofuran, 15.2 ml) was added thereto and the mixture was stirredfor 30 minutes. A solution of 2-(phenylsulfonyl)-3-phenyloxaziridine(2.16 g) in anhydrous tetrahydrofuran (10 ml) was added to the reactionmixture, which was stirred at −70˜−60° C. for 4 hours. A saturatedaqueous ammonium chloride solution was added to the reaction mixture,which was extracted with ethyl acetate. The organic layer was washedwith water and brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the obtained residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=3:7→2:3) to give thetitle compound (1.30 g) having the following physical data.

TLC:Rf 0.30 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.31 (s, 1H), 7.19 (t, J=8.1 Hz,1H), 4.38-4.19 (m, 3H), 3.18 (br, 1H), 2.77-2.51 (m, 2H), 2.37 (m, 1H),2.03 (m, 1H), 1.31 (t, J=7.8 Hz, 3H).

REFERENCE EXAMPLE 8

Ethyl 4-[N-(2,6-dichlorophenyl)carbamoyl]-2-methoxymethoxybutanoate

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 7 (650 mg) in methylene chloride (5 ml) were addeddiisopropylethylamine (2.1 ml) and chloromethyl methyl ether (0.70 ml)in ice bath and the mixture was stirred at room temperature for 12hours. Ethyl acetate was added to the reaction mixture, which was washedwith 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, water and brine sequentially, and dried overanhydrous magnesium sulfate. The solvent was evaporated and the obtainedresidue was purified by column chromatography on silica gel (ethylacetate:hexane=3:7→2:3) to give the title compound (330 mg) having thefollowing physical data.

TLC:Rf 0.43 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.31 (s, 1H), 7.19 (t, J=8.1 Hz,1H), 4.79-4.68 (m, 2H), 4.49 (m, 1H), 4.21 (q, J=7.8 Hz, 2H), 3.43 (s,3H), 2.72-2.48 (m, 2H), 2.40-2.08 (m, 2H), 1.32 (t, J=7.8 Hz, 3H).

REFERENCE EXAMPLE 9

4-[N-(2,6-dichlorophenyl)carbamoyl]-2-methoxymethoxybutanol

By the same procedure as described in Reference Example 3 using thecompound prepared in Reference Example 8 instead of the compoundprepared in Reference Example 2, the title compound having the followingphysical data was obtained.

TLC:Rf 0.22 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.31 (s, 1H), 7.19 (t, J=8.1 Hz,1H), 4.91-4.68 (m, 2H), 3.78 (m, 1H), 3.78-3.50 (m, 2H), 3.46 (s, 3H),3.01 (br, 1H), 2.65-2.50 (m, 2H), 2.05-1.86 (m, 2H).

REFERENCE EXAMPLE 10

4-[N-(2,6-dichlorophenyl)carbamoyl]-2-methoxymethoxybutyl4-methylbenzensulfonate

Under an atmosphere of argon, a solution of the compound prepared inReference Example 9 (190 mg) in pyridine (5 ml) was cooled to 0° C.p-toluenesulfonyl chloride (180 mg) was added thereto and the mixturewas stirred at room temperature for 12 hours. The reaction mixture wasdiluted with ethyl acetate, washed with 1N hydrochloric acid, water, asaturated aqueous sodium hydrogen carbonate solution, water and brinesequentially, and dried over anhydrous magnesium sulfate. The solventwas evaporated to give the title compound having the following physicaldata.

TLC:Rf 0.44 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.80 (d, J=8.1 Hz, 2H), 7.42-7.32 (m, 5H), 7.19 (m, 1H),4.75-4.60 (m, 2H), 4.08-4.02 (m, 2H), 3.97 (m, 1H), 3.38 (s, 3H),2.61-2.47 (m, 2H), 2.45 (s, 3H), 2.02-1.80 (m, 2H).

REFERENCE EXAMPLE 11

1-(2,6-dichlorophenyl)-5-methoxymethoxypiperidin-2-one

By the same procedure as described in Example 1 using the compoundprepared in Reference Example 10 instead of the compound prepared inReference Example 4, the title compound having the following physicaldata was obtained.

TLC:Rf 0.39 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.41-7.38 (m, 2H), 7.22 (m, 1H), 4.79-4.74 (m, 2H), 4.19(m, 1H), 3.67 (dd, J=12.0, 4.5 Hz, 1H), 3.54 (dd, J=12.0, 5.4 Hz, 1H),3.41 (s, 3H), 2.87-2.74 (m, 1H), 2.56 (dt, J=17.7, 6.3 Hz, 1H),2.20-2.10 (m, 2H).

REFERENCE EXAMPLE 12

1-(2,6-dichlorophenyl)-5-hydroxypiperidin-2-one

The compound prepared in Reference Example 11 (178 mg) dissolved in amixed solvent of methanol (5 ml) and water (1 ml). Concentratedhydrochloric acid (0.12 ml) was added thereto and the mixture wasstirred at 70° C. for 6 hours. The reaction mixture was neutralized witha saturated aqueous sodium hydrogen carbonate solution and concentrated.The residue was dissolved in ethyl acetate, washed with water and brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand washed with isopropyl ether to give the title compound (102 mg)having the following physical data.

TLC:Rf 0.21 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.42-7.38 (m, 2H), 7.22 (m, 1H), 4.38 (m, 1H), 3.74 (dd,J=12.0, 4.2, 1H), 3.45 (dd, J=12.0, 4.8 Hz, 1H), 2.83 (ddd, J=18.0, 8.4,6.6 Hz, 1H), 2.59 (dt, J=18.0, 6.3 Hz, 1H), 2.20-2.07 (m, 2H), 1.91 (d,J=4.8 Hz, 1H).

EXAMPLE 8

1-(2,6-dichlorophenyl)-5-(2,4-difluorophenoxy)piperidin-2-one

Under an atmosphere of argon, the compound prepared in Reference Example12 (100 mg) was dissolved in tetrahydrofuran (5 ml). 2,4-difluorophenol(64 mg) and triphenylphosphine (232 mg) were added thereto and thereaction mixture was iced. Diethyl azodicarboxylate (40% solution intoluene, 0.35 ml) was added to the reaction mixture, which was stirredat room temperature for 12 hours. The reaction mixture was concentratedand the obtained residue was purified by column chromatography on silicagel (ethyl acetate:hexane=3:7) to give the compound of the presentinvention (51 mg) having the following physical data.

TLC:Rf 0.41 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.43-7.38 (m, 2H), 7.23 (m, 1H), 7.04 (m, 1H), 6.93-6.76(m, 2H), 4.77 (m, 1H), 3.83-3.68 (m, 2H), 2.92 (ddd, J=17.4, 9.6, 6.0Hz, 1H), 2.61 (dt, J=17.4, 6.0 Hz, 1H), 2.41-2.18 (m, 2H).

EXAMPLE 8(1)

1-(2,6-dichlorophenyl)-5-(2,4-difluorothiophenoxy)piperidin-2-one

By the same procedure as described in Example 8 using2,4-difluorothiophenol instead of 2,4-difluorophenol, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.47 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.60 (m, 1H), 7.40-7.35 (m, 2H), 7.21 (m, 1H), 6.94-6.83(m, 2H), 3.65 (m, 1H), 3.62-3.53 (m, 2H), 2.81 (ddd, J=17.7, 6.0, 4.8Hz, 1H), 2.61 (ddd, J=17.7, 9.6, 6.3 Hz, 1H), 2.28 (m, 1H), 1.98 (m,1H).

EXAMPLE 9

1-(2,6-dichloro-4-nitrophenyl)-5-benzylpiperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Example 2 using2,6-dichloro-4-nitroaniline instead of 2,6-dichloroaniline, the compoundof the present invention having the following physical data wasobtained.

TLC:Rf 0.63 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 8.26-8.23 (m, 2H), 7.34-7.17 (m, 5H), 3.38-3.32 (m, 2H),2.80-2.65 (m, 3H), 2.60-2.36 (m, 2H), 2.08-2.01 (m, 1H), 1.80-1.67 (m,1H).

EXAMPLE 9(1)

1-(2,6-dichloro-4-nitrophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Example 2 using2,6-dichloro-4-nitroaniline instead of 2,6-dichloroaniline and2,4-difluorobenzylbromide instead of benzylbromide, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.57 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 8.26 (dd, J=2.3 Hz, 4.1 Hz, 2H), 7.18-7.10 (m, 1H),6.87-6.78 (m, 2H), 3.40-3.29 (m, 2H), 2.74 (d, J=6.9 Hz, 2H), 2.68 (dd,J=3.3 Hz, 5.7 Hz, 1H), 2.60-2.48 (m, 1H), 2.45-2.32 (m, 1H), 2.08-1.97(m, 1H), 1.82-1.68 (m, 1H).

EXAMPLE 10

1-(2,6-dichloro-4-aminophenyl)-5-benzylpiperidin-2-one

The compound prepared in Example 9 (421 mg) was dissolved in a mixedsolvent of acetic acid (11 ml) and water (2 ml). Iron powder (470 mg)was added thereto and the mixture was stirred at room temperature for 10minutes. The reaction mixture was diluted with ethyl acetate andfiltrated through Celite (proprietary name). The filtrate wasconcentrated and filtrated with Floridil (proprietary name). Thefiltrate was concentrated and the obtained residue was washed withisopropyl ether to give the compound of the present invention (373 mg)having the following physical data.

TLC:Rf 0.14 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.33-7.17 (m, 5H), 6.62-6.59 (m, 2H), 3.87 (s, 2H),3.35-3.26 (m, 2H), 2.74-2.60 (m, 3H), 2.54-2.42 (m, 1H), 2.38-2.30 (m,1H), 2.01-1.92 (m, 1H), 1.73-1.62 (m, 1H).

EXAMPLE 10(1)

1-(2,6-dichloro-4-aminophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 10 using the compoundprepared in Example 9(1), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.21 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.18-7.10 (m, 1H), 6.85-6.76 (m, 2H), 6.60-6.58 (m, 2H),3.92 (s, 2H), 3.31 (d, J=7.8 Hz, 2H), 2.72-2.62 (m, 3H), 2.55-2.43 (m,1H), 2.38-2.29 (m, 1H), 1.99-1.92 (m, 1H), 1.75-1.65 (m, 1H).

EXAMPLE 11

1-[2,6-dichloro-4-(N-(4-methylimidazol-5-ylmethyl)amino)phenyl]-5-benzylpiperidin-2-one

The compound prepared in Example 10 (100 mg), 4-methyl-5-formylimidazole(158 mg) and anhydrous magnesium sulfate (35 mg) were suspended intoluene (3 ml) and the mixture was refluxed for 1.5 hours. The reactionmixture was concentrated and the residue was suspended in methanol (3ml). Sodium borohydride (55 mg) was added to the suspension, which wasstirred for 30 minutes. The reactioin mixture was diluted with ethylacetate and water and extracted with ethyl acetate. The organic layerwas washed with water and brine and dried over anhydrous sodium sulfate.The solvent was evaporated and the obtained residue was washed withethyl acetate to give the compound of the present invention (93 mg)having the following physical data.

TLC:Rf 0.28 (chloroform:methanol=9:1);

NMR (DMSO-d₆):d 11.70 (s, 1H), 7.42 (s, 1H), 7.30-7.15 (m, 5H), 6.71 (s,2H), 6.43 (t, J=5.1 Hz, 1H), 4.00 (s, 2H), 3.22-3.12 (m, 2H), 2.66 (d,J=7.5 Hz, 2H), 2.41-2.23 (m, 3H), 2.15 (s, 3H), 1.90-1.80 (m, 1H),1.62-1.48 (m, 1H).

EXAMPLE 11(1)

1-[2,6-dichloro-4-(N-methylamino)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 11 using paraformaldehydeinstead of 4-methyl-5-formylimidazole, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.44 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 7.18-7.10 (m, 1H), 6.85-6.76 (m, 2H), 6.52-6.50 (m, 2H),4.17-4.08 (m, 1H), 3.32 (d, J=8.1 Hz, 2H), 2.76 (d, J=4.8 Hz, 3H),2.72-2.61 (m, 3H), 2.55-2.43 (m, 11H), 2.37-2.28 (m, 1H), 2.00-1.90 (m,1H), 1.75-1.62 (m, 1H).

EXAMPLE 12

1-[2,6-dichloro-4-(2-phenylacetylamino)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one

A solution of the compound prepared in Example 10(1) (115 mg) andtriethylamine (50 μl) in methylene chloride (3 ml) was iced.Phenylacetyl chloride (48 μl) was added thereto and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture, which was extracted with methylene chloride. The organic layerwas washed with 1N hydrochloric acid, 1N aqueous sodium hydroxidesolution, water and brine sequentially, and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the obtained residuewashed with isopropyl ether to give the compound of the presentinvention (104 mg) having the following physical data.

TLC:Rf 0.36 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 9.03 (s, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz,1H), 7.32-7.28 (m, 5H), 7.16-7.08 (m, 1H), 6.85-6.76 (m, 2H), 3.58 (s,2H), 3.32-3.29 (m, 2H), 2.78-2.70 (m, 3H), 2.63-2.51 (m, 1H), 2.44-2.30(m, 1H), 2.05-1.94 (m, 1H), 1.80-1.70 (m, 1H).

EXAMPLE 12(1)

1-(2,6-dichloro-4-acetylaminophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 12 using acetyl chlorideinstead of phenylacetyl chloride, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.23 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 9.12 (s, 1H), 7.35 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.3 Hz,1H), 7.17-7.09 (m, 1H), 6.86-6.77 (m, 2H), 3.31 (d, J=8.4 Hz, 2H),2.75-2.67 (m, 3H), 2.57 (m, 1H), 2.37 (m, 1H), 2.05-1.94 (m, 4H), 1.73(m, 1H).

EXAMPLE 13

1-[2,6-dichloro-4-(N-methyl-2-phenylacetylamino)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one

To solution of the compound prepared in Example 12 (65 mg) inN,N-dimethylformamide (1.3 ml) were added sodium hydride (5 mg) andmethyl iodide (9 μl) and the mixture was stirred at room temperature for1 hour. Water was added to the reaction mixture, which was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous sodium thiosulfate solution, 1N hydrochloric acid and brine anddried over anhydrous sodium sulfate. The solvent was evaporated and theobtained residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:1) to give the compound of the present invention(34 mg) having the following physical data.

TLC:Rf 0.30 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.26-7.01 (m, 8H), 6.87-6.79 (m, 2H), 3.57 (s, 2H), 3.36(d, J=9.0 Hz, 2H), 3.25 (s, 3H), 2.76-2.65 (m, 3H), 2.59-2.47 (m, 1H),2.46-2.32 (m, 1H), 2.05-1.96 (m, 1H), 1.81-1.71 (m, 1H).

EXAMPLE 14

(3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

Under an atmosphere of argon, a solution of the compound prepared inExample 1(1) (130 mg) in anhydrous tetrahydrofuran (10 ml) was cooled to−78° C. Lithium bis(trimethylsilyl)amide (1.0M solution intetrahydrofuran, 0.39 ml) was added thereto and the mixture was stirredfor 30 minutes. Methyl iodide (24 μl) was added to the reaction mixture,which was stirred at −70˜−60° C. for 30 minutes. A saturated aqueousammonium chloride solution was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine and dried over anhydrous magnesium sulfate. The solvent wasevaporated and the obtained residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:4) and washed withisopropyl ether-hexane to give the compound of the present invention (29mg) having the following physical data and the compound of the presentinvention (20 mg) represented in Example 14a.

TLC:Rf 0.58 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.36 (d, J=7.8 Hz, 2H), 7.22-7.08 (m, 2H), 6.88-6.77 (m,2H), 3.42-3.24 (m, 2H), 2.67 (d, J=7.2 Hz, 2H), 2.61-2.35 (m, 2H), 2.02(m, 1H), 1.51 (m, 1H), 1.30 (d, J=7.2 Hz, 3H).

EXAMPLE 14a

(3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

TLC:Rf 0.50 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.34 (m, 2H), 7.23-7.12 (m, 2H), 6.88-6.77 (m, 2H),3.37 (d, J=7.5 Hz, 2H), 2.83-2.63 (m, 3H), 2.54 (m, 1H), 1.91 (ddd,J=13.8, 9.3, 6.3 Hz, 1H), 1.77 (dt, J=13.8, 4.5 Hz, 1H), 1.33 (d, J=7.5Hz, 3H).

EXAMPLE 14(1)

(3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-ethylpiperidin-2-one

By the same procedure as described in Example 14 using ethyl iodideinstead of methyl iodide, the compound of the present invention havingthe following physical data and the compound of the present inventionrepresented in Example 14(1)a were obtained.

TLC:Rf 0.60 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.36 (d, J=8.4 Hz, 2H), 7.21-7.08 (m, 2H), 6.87 (m, 2H),3.36 (t, J=11.4 Hz, 1H), 3.23 (ddd, J=11.4, 4.8, 2.1 Hz, 1H), 2.78-2.61(m, 2H), 2.51-2.33 (m, 2H), 2.00 (m, 1H), 1.89 (m, 1H), 1.76 (m, m, 1H),1.57 (m, 1H), 0.97 (t, J=7.5 Hz, 3H).

EXAMPLE 14(1)a

(3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-ethylpiperidin-2-one

TLC:Rf 0.56 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.41-7.36 (m, 2H), 7.23-7.12 (m, 2H), 6.87-6.77 (m, 2H),3.41 (dd, J=11.7, 5.7 Hz, 1H), 3.32 (dd, J=11.7, 8.4 Hz, 1H), 2.84-2.70(m, 2H), 2.60-2.42 (m, 2H), 2.02-1.76 (m, 3H), 1.62 (m, 1H), 0.96 (t,J=7.8 Hz, 3H).

EXAMPLE 14(2)

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methoxymethylpiperidin-2-one

By the same procedure as described in Example 14 using bromomethylmethyl ether instead of methyl iodide, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.51 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.40-7.34 (m, 2H), 7.22-7.08 (m, 2H), 6.87-6.76 (m, 2H),3.80-3.68 (m, 2H), 3.45-3.21 (m, 5H), 2.98-2.34 (m, 4H), 2.12 (m, 1H),1.90-1.65 (m, 1H).

EXAMPLE 15

1-(2,6-dichlorophenyl)-5,5-bis(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 3→Example 2using ethyl4-[N-(2,6-dichlorophenyl)carbamoyl]-2,2-bis(2,4-difluorobenzyl)butanoateinstead of the compound prepared in Reference Example 2, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.30 (hexane:ethyl acetate=2:1);

NMR (DMSO-d₆):d 7.60-7.50 (m, 2H), 7.42-7.30 (m, 3H), 7.25-7.15 (m, 2H),7.08-6.98 (m, 2H), 3.34 (s, 2H), 3.00 (d, J=14.1 Hz, 2H), 2.71 (d,J=14.1 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.58 (t, J=6.9 Hz, 2H).

EXAMPLES 16(1)˜16(13)

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Example 2 using the corresponding aminederivatives and the corresponding halobenzyl derivatives, the followingcompounds of the present invention were obtained.

EXAMPLE 16(1)

1-(4-bromo-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.40 (ethyl acetate:hexane=3:1);

NMR (CDCl₃):d 7.24 (s, 2H), 7.15-7.07 (m, 1H), 6.87-6.73 (m, 2H),3.27-3.10 (m, 2H), 2.73-2.60 (m, 3H), 2.55-2.42 (m, 1H), 2.35-1.92 (m,8H), 1.74-1.60 (m, 1H).

EXAMPLE 16(2)

1-(2-methylnaphthalene-1-yl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.27 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 7.88-7.80 (m, 1H), 7.78-7.60 (m, 2H), 7.53-7.33 (m, 3H),7.19-7.07 (m, 1H), 6.88-6.72 (m, 2H), 3.53-3.25 (m, 2H), 2.88-2.25 (m,8H), 2.14-2.04 (m, 1H), 1.93-1.68 (m, 1H).

EXAMPLE 16(3)

1-(2,6-dimethylphenyl)-5-(2-methoxyethoxymethoxybenzyl)piperidin-2-one

TLC:Rf 0.28 (ethyl acetate:hexane=7:3);

NMR (CDCl₃):d 7.22-7.04 (m, 6H), 6.93 (m, 1H), 5.29 (s, 2H), 3.78-3.72(m, 2H), 3.54-3.49 (m, 2H), 3.37 (s, 3H), 3.31-3.17 (m, 2H), 2.70 (d,J=6.9 Hz, 2H), 2.67 (ddd, J=18.3, 5.7, 3.0 Hz, 1H), 2.49 (ddd, J=18.3,12.0, 6.6 Hz, 1H), 2.35 (m, 1H), 2.22 (s, 3H), 2.10 (s, 3H), 2.00 (m,1H), 1.66 (m, 1H).

EXAMPLE 16(4)

1-(2,6-dichlorophenyl)-5-(4-nitrobenzyl)piperidin-2-one

TLC:Rf 0.40 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 8.19 (d, J=8.7 Hz, 2H), 7.45-7.32 (m, 4H), 7.26-7.18 (m,1H), 3.40-3.30 (m, 2H), 2.90-2.86 (m, 2H), 2.75-2.65 (m, 1H), 2.61-2.35(m, 2H), 2.08-1.93 (m, 1H), 1.86-1.68 (m, 1H).

EXAMPLE 16(5)

1-(2,6-dichlorophenyl)-5-(2-cyanobenzyl)piperidin-2-one

TLC:Rf 0.39 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.82 (m, 1H) 2.00 (m, 1H) 2.52 (m, 2H) 2.70 (m, 1H) 2.96(m, 2 H)3.40 (m, 2H)7.21 (m, 1H)7.37 (m, 4H)7.56 (m, 1H)7.67 (m, 1H).

EXAMPLE 16(6)

1-(2,6-dimethylphenyl)-5-(2-bromobenzyl)piperidin-2-one

TLC:Rf 0.35 (ethyl acetate);

NMR (CDCl₃):d 1.75 (m, 1H) 2.04 (m, 1H) 2.12 (s, 3H) 2.23 (s, 3H) 2.50(m, 2H) 2.69 (m, 1H) 2.81 (m, 2H) 3.27 (m, 2H) 7.10 (m, 4H) 7.21 (m, 2H)7.56 (dd, J=7.97, 1.10 Hz, 1H).

EXAMPLE 16(7)

1-(thiazol-2-yl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.73 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 1.62 (m, 1H) 1.95 (m, 1H) 2.26 (m, 1H) 2.73 (m, 4H) 3.66(dd, J=13.00, 10.44 Hz, 1H) 4.51 (m, 1H) 6.85 (m, 2H) 7.01 (d, J=3.48Hz, 1H) 7.16 (m, 1H) 7.51 (d, J=3.66 Hz, 1H).

EXAMPLE 16(8)

1-(2,6-dichlorophenyl)-5-(2-methoxymethoxymethylbenzyl)piperidin-2-one

TLC:Rf 0.61 (hexane:ethyl acetate=2:3);

NMR (CDCl₃):d 1.75 (m, 1H), 2.01 (m, 1H), 2.60-2.36 (m, 2H), 2.86-2.63(m, 3H), 3.45-3.32 (m, 5H), 4.60 (d, J=9.6 Hz, 1H), 4.64 (d, J=9.6 Hz,1H), 4.69 (s, 2H), 7.32-7.17 (m, 4H), 7.41-7.36 (m, 3H).

EXAMPLE 16(9)

1-(4-t-butoxycarbonylamino-2-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.33 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 7.58 (s, 1H), 7.20-7.02 (m, 3H), 6.90-6.70 (m, 3H),3.45-3.30 (m, 2H), 2.78-2.42 (m, 4H), 2.40-2.20 (m, 1H), 2.02-1.90 (m,1H), 1.78-1.60 (m, 1H), 1.51 (s, 9H).

EXAMPLE 16(10)

1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.48 (hexane:acetone=2:3);

NMR (CDCl₃):d 7.66-7.53 (m, 2H), 7.20-7.08 (m, 1H), 6.93-6.74 (m, 2H),6.45-6.32 (m, 1H), 3.13-3.28 (m, 2H), 2.73-2.69 (m, 2H), 2.67-2.61 (m,1H), 2.55-2.45 (m, 1H), 2.40-2.28 (m, 1H), 2.03-1.90 (m, 1H), 1.75-1.65(m, 1H), 1.50 (s, 9H).

EXAMPLE 16(11)

1-(3-t-butoxycarbonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.29 (hexane:ethyl acetate=1:1); NMR (CDCl₃):d 7.53-7.47 (m, 1H),7.33-7.28 (m, 1H), 7.18-7.08 (m, 1H), 7.06-7.01 (m, 1H), 6.84-6.72 (m,3H), 3.43-3.25 (m, 2H), 2.71-2.20 (m, 5H), 2.04-1.91 (m, 1H), 1.76-1.64(m, 1H), 1.50-1.49 (m, 9H).

EXAMPLE 16(12)

1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one

TLC:Rf 0.55 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 1.49 (s, 9H) 1.72 (m, 1H) 1.98 (m, 1H) 2.38 (m, 1H) 2.52(m, 1 H) 2.71 (m, 3H) 3.33 (d, J=8.00 Hz, 2H) 7.06 (m, 2H) 7.19 (m, 2H)7.35 (m, 3H).

EXAMPLE 16(13)

1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.56 (hexane:ethyl acetate=1:2);

NMR (CDCl₃):d 1.71 (m, 1H) 1.98 (m, 1H) 2.35 (m, 1H) 2.51 (m, 1H) 2.68(m, 3 H) 3.32 (m, 2H) 6.83 (m, 2H) 7.14 (m, 1H) 7.54 (m, 2H).

EXAMPLE 17

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-5-hydroxymethylpiperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Example 2 using 4,4-bis(ethoxycarbonyl)-5-phenylpentanoic acidinstead of ethyl glutaryl chloride, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.37 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 7.43-7.37 (m, 2H), 7.30-7.20 (m, 2H), 6.90-6.78 (m, 2H),3.70 (d, J=5.0 Hz, 2H), 3.55 (d, J=12.0 Hz, 1H), 3.31 (dd, J=12.0, 1.5Hz, 1H), 2.92 (dd, J=13.8, 1.8 Hz, 1H), 2.83 (dd, J=13.8, 1.8 Hz, 1H),2.69 (ddd, J=18.9, 6.9, 5.1 Hz, 1H), 2.56 (ddd, J=18.9, 9.9, 6.9 Hz,1H), 1.93-1.75 (m, 3H).

EXAMPLE 18

1-(2,6-dimethylphenyl)-5-(3-phenylprop-1-enyl)-5-hydroxymethylpiperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 2→Reference Example 3→Example 2 using 2,6-dimethylaniline and((1E)-3-bromoprop-1-enyl)benzene, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.33 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 7.38-7.18 (m, 5H), 7.16-7.04 (m, 3H), 6.42 (d, J=15.9,1H), 6.18 (dt, J=15.9, 7.5 Hz, 1H), 3.34 (m, 1H), 3.21 (dd, J=11.9, 9.3Hz, 1H), 2.68 (m, 1H), 2.57 (m, 1H), 2.43-2.25 (m, 2H), 2.23-2.02 (m,8H), 1.69 (m, 1H).

REFERENCE EXAMPLE 13

3-(2,6-dichlorophenylaminocarbonylamino)-2-(2,4-difluorophenylmethyl)propanoicacid ethyl ester

Under an atmosphere of argon, to a solution of3-amino-2-(2,4-difluorophenylmethyl)propanoic acid ethyl ester (837 mg)and 2,6-dichlorophenyl isocyanate (617 mg) in tetrahydrofuran (20 ml)was added triethylamine (415 μl) at 0° C. The reaction mixture wasstirred at room temperature for 2 hours. To the reaction mixture werewater and ethyl acetate. The organic layer was washed with brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspowdered with isopropyl ether and methanol to give the title compound(803 mg) having the following physical data.

TLC:Rf 0.37 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 7.38 (d, J=8.1 Hz, 2H), 7.21-7.11 (m, 2H), 6.82-6.70 (m,2H), 6.15 (br, 1H), 5.06 (br, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.53 (m, 1H),3.39 (m, 1H), 3.02-2.79 (m, 3H), 1.14 (t, J=7.2 Hz, 3H).

EXAMPLE 19

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

By the same procedure as described in Reference Example 3→Example 2using the compound prepared in Reference Example 19, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.32 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 7.41-7.35 (m, 2H), 7.22-7.13 (m, 2H), 6.88-6.77 (m, 2H),4.98 (br, 1H), 3.45-3.35 (m, 3H), 3.19 (m, 1H), 2.88-2.72 (m, 2H), 2.59(m, 1H).

EXAMPLE 20

1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

By the same procedure as described in Reference Example 13→Example 19using 4-bromo-2,6-dichlorophenyl isocyanate instead of2,6-dichlorophenyl isocyanate, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.47 (ethyl acetate:toluene=2:1);

NMR (CDCl₃):d 2.15 (s, 3H) 2.25 (s, 3H) 2.51 (m, 1H) 2.74 (m, J=7.83,7.83 Hz, 2 H) 3.27 (m, 4H) 4.88 (m, J=3.02 Hz, 1H) 6.83 (m, 2H) 7.13 (m,1H) 7.22 (s, 2H).

REFERENCE EXAMPLE 14

3-(2,6-dichlorophenylaminocarbonyloxy)-2-(2,4-difluorophenylmethyl)propanoicacid ethyl ester

By the same procedure as described in Reference Example 13 using3-hydroxy-2-(2,4-difluorophenylmethyl)propanoic acid benzyl esterinstead of 3-amino-2-(2,4-difluorophenylmethyl)propanoic acid ethylester, the title compound having the following physical data wasobtained.

TLC:Rf 0.43 (hexane:ethyl acetate=7:3);

NMR (CDCl₃):d 2.96 (m, 3H) 4.37 (m, 2H) 5.09 (s, 2H) 6.20 (m, 1H) 6.74(m, 2 H) 7.06 (m, 1H) 7.23 (m, 3H) 7.35 (m, 5H).

REFERENCE EXAMPLE 15

3-(2,6-dichlorophenylaminocarbonyloxy)-2-(2,4-difluorophenylmethyl)propanoicacid

To a solution of the compound prepared in Reference Example 14 (256 mg)in methanol (5 ml) was added 5% palladium-carbon (50 mg). The mixturewas stirred at room temperature for 30 minutes under an atmosphere ofhydrogen. The reaction mixture was filtrated through Celite (proprietaryname) and concentrated to give the title compound having the followingphysical data.

TLC:Rf 0.15 (hexane:ethyl acetate=2:3);

NMR (CDCl₃):d 3.03 (m, 3H) 4.36 (m, 2H) 6.44 (m, 1H) 6.81 (m, 2H) 7.17(m, 2 H) 7.35 (m, 2H).

REFERENCE EXAMPLE 16

3-(2,6-dichlorophenylaminocarbonyloxy)-2-(2,4-difluorophenylmethyl)propanoicacid

By the same procedure as described in Reference Example 5 using thecompound prepared in Reference Example 15 instead of4-amino-3,5-dichlorobenzoic acid, the title compound having thefollowing physical data was obtained.

TLC:Rf 0.35 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 2.12 (m, 1H) 2.44 (t, J=6.59 Hz, 1H) 2.65 (m, 2H) 3.60 (m,2H) 4.17 (m, 1H) 4.32 (m, 1H) 6.33 (m, 1H) 6.80 (m, 2H) 7.15 (m, 2H)7.40 (m, 2H).

EXAMPLE 21

3-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-1,3-tetrahydrooxazin-2-one

By the same procedure as described in Example 2 using the compoundprepared in Reference Example 16, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.39 (ethyl acetate:toluene=1:4);

NMR (CDCl₃):d 2.64 (m, 1H) 2.86 (m, 2H) 3.40 (m, J=10.99, 7.42 Hz, 1H)3.56 (m, 1H) 4.19 (dd, J=10.99, 7.69 Hz, 1H) 4.39 (m, 1H) 6.85 (m, 2H)7.23 (m, 2H) 7.41 (m, 2H).

REFERENCE EXAMPLE 17

2-((2,6-dichlorophenyl)aminocarbonylmethylamino)-3-(2,4-difluorophenyl)propanoicacid methyl ester

To a solution of 2-amino-3-(2,4-difluorophenyl)propanoic acid methylester (1 g) in dimethylformamide (10 ml) were added triethylamine (1.1ml) and N-(2,6-dichlorophenyl)-2-bromoacetamide (1.69 g) at roomtemperature. The reaction mixture was stirred at 90° C. for 3 hours. Tothe reaction mixture were added water and ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=7:3→3:2) to give the title compound(0.92 g) having the following physical data.

TLC:Rf 0.50 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 2.31 (m, 1H) 2.86 (m, 1H) 3.09 (m, 1H) 3.20 (d, J=17.86Hz, 1H) 3.57 (m, 2H) 3.77 (s, 3H) 6.69 (m, 2H) 7.16 (m, 2H) 7.33 (d,J=8.24 Hz, 2H) 8.25 (s, 1H).

REFERENCE EXAMPLE 18

2-(N-((2,6-dichlorophenyl)aminocarbonyl)methyl-N-acetylamino)-3-(2,4-difluorophenyl)propanoicacid methyl ester

To a solution of the compound prepared in Reference Example 17 (130 mg)in dichloromethane were added acetyl chloride (24 μl) and triethylamine(42 μl) at 0° C. The reaction mixture was stirred for 15 minutes. To thereaction mixture were added water and ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated to give the title compound (93 mg) having the followingphysical data.

TLC:Rf 0.52 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 2.18 (s, 3H) 3.52 (m, 3H) 3.87 (s, 3H) 4.02 (m, 2H) 6.87(m, 2H) 7.16 (m, 2H)7.39 (m, 2H) 10.06 (s, 1H).

EXAMPLE 22

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-4-acetylpiperazin-2-one

TLC:Rf 0.40 (toluene:ethyl acetate=3:7);

NMR (CDCl₃):d 2.05 and 1.80 (s and s, 3H), 3.45-3.05 (m, 3H), 4.12 and3.97 (m, 1H), 4.27 and 3.96 (d and d, J=18.1 Hz and J=19.5 Hz, 1H), 5.08and 4.43 (d and d, J=19.5 Hz, and J=18.1 Hz, 1H), 5.35 and 4.39 (m, 1H),6.91-6.77 (m, 2H), 7.34-7.13 (m, 2H), 7.46-7.40 (m, 2H).

REFERENCE EXAMPLE 19

2-((2,6-dichlorophenyl)aminocarbonyl)methyloxy)-3-(2,4-difluorophenyl)propanoicacid ethyl ester

Under an atmosphere of argon, to a solution of1-((2,6-dichlorophenyl)aminocarbonyl)methyloxyacetic acid methyl ester(290 mg) and 2,4-difluorobenzyl bromide (134 μl) in tetrahydrofuran (10ml) was added lithium bis(trimethylsilyl)amide (1.0M solution intetrahydrofuran, 2.09 ml) at −78° C. The reaction mixture was stirred atbelow −60° C. for 15 minutes. A saturated aqueous ammonium chloridesolution was added to the reaction mixture, which was extracted ethylacetate. The extract was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel (hexane:ethylacetate=4:1→7:3) to give the title compound (53 mg) having the followingphysical data.

TLC:Rf 0.56 (toluene:ethyl acetate=1:1);

NMR (CDCl₃):d 7.96 (s, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.32-7.15 (m, 2H),6.85-6.72 (m, 2H), 4.34-4.04 (m, 5H), 3.27 (m, 1H), 3.08 (m, 1H), 1.28(t, J=7.8 Hz, 3H).

EXAMPLE 23

4-(2,6-dichlorophenyl)-6-(2,4-difluorobenzyl)morpholin-3-one

By the same procedure as described in Reference Example 3→Example 2using the compound prepared in Reference Example 19, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.49 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 2.92 (m, 2H) 3.29 (dd, J=11.40, 2.88 Hz, 1H) 3.70 (t,J=11.40 Hz, 1 H) 4.19 (m, 1H) 4.30 (d, J=17.03 Hz, 1H) 4.48 (d, J=17.03Hz, 1H) 6.82 (m, 2H) 7.24 (m, 2H) 7.40 (m, 2H).

REFERENCE EXAMPLE 20

4-((2,6-dichlorophenyl)aminocarbonyl)-2-((2,4-difluorophenyl)hydroxymethyl)butanoic acid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 1 (1.52 g) in tetrahydrofuran (15 ml) was addedlithium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 11.0ml) at −78° C. The mixture was stirred for 30 minutes and2,4-difluorobenzaldehyde (602 μl) was added thereto. The reactionmixture was stirred at −60° C. for 4 hours. An aqueous ammonium chloridesolution was added to the reaction mixture, which was extracted ethylacetate. The extract was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel (hexane:ethylacetate=7:3) to give the title compound (1.90 g) having the followingphysical data.

TLC:Rf 0.36 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 7.53-7.32 (m, 3H), 7.18 (m, 1H), 7.04 (s, 1H), 6.85 (m,1H), 6.79 (m, 1H), 5.23 and 5.18 (m and m, 1H), 4.22-4.00 (m, 2H), 3.37and 3.28 (m and d, J=6.9 Hz, 1H), 2.99 (m, 1H), 2.65-2.32 (m, 2H),2.30-1.85 (m, 2H), 1.30-1.00 (m, 3H).

REFERENCE EXAMPLE 21

4-((2,6-dichlorophenyl)aminocarbonyl)-2-(1-(2,4-difluorophenyl)-1-(t-butyldimethylsilyloxy)methyl)butanoicacid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 20 (1.85 g) in dimethylformamide (15 ml) were addedimidazole (1.69 g) and t-butyldimethylsilyl chloride (1.37 g) at roomtemperature. The reaction mixture was stirred at room temperature for 36hours. The reaction mixture was diluted with ethyl acetate, washed with1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1) to give thetitle compound (2.16 g) having the following physical data.

TLC:Rf 0.73 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 7.46-7.32 (m, 3H), 7.20-7.00 (m, 2H), 6.86 (m, 1H), 6.76(m, 1H), 5.23 and 5.18 (d, J=5.7 Hz and d, J=7.5 Hz, 1H), 4.27-3.98 (m,2H), 3.02-1.75 (m, 5H), 1.32 and 1.17 (t, J=6.9 Hz and t, J=6.9 Hz, 3H),0.86 and 0.81 (s and s, 9H), 0.046 and 0.016 (s and s, 3H), −0.21 and−0.27 (s and s, 3H).

REFERENCE EXAMPLE 22

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)1-(t-butyldimethylsilyloxy)methyl)piperidin-2-one

By the same procedure as described in Reference Example 3→Example 2using the compound prepared in Reference Example 21, the title compoundhaving the following physical data was obtained.

TLC:Rf 0.39 (hexane:ethyl acetate=7:3);

NMR (CDCl₃):d 7.49-7.32 (m, 3H), 7.20 (m, 1H), 6.89 (m, 1H), 6.78 (m,1H), 4.97-4.90 (m, 1H), 3.54 and 3.47 (t, J=11.4 Hz and t, J=11.4 Hz,1H), 3.38 and 3.12 (m and ddd, J=11.4, 4.8, 1.8 Hz, 1H), 2.68 (m, 1H),2.49 (m, 1H), 2.36 (m, 1H), 2.12 (m, 1H), 1.86-1.68 (m, 1H), 0.89 and0.86 (s and s, 9H), 0.046 and 0.020 (s and s, 3H), −0.19 and −0.22 (sand s, 3H).

EXAMPLE 24

1-(2,6-dichlorophenyl)-5-((2,4-difluorophenyl)hydroxymethyl)piperidin-2-one

Under an atmosphere of argon, to a solution the compound prepared inReference Example 22 (870 mg) in tetrahydrofuran (15 ml) was addedt-butylammonium fluoride 3H₂O (1.10 g) at room temperature. The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas diluted with ethyl acetate, washed with 1N hydrochloric acid, water,a saturated aqueous sodium hydrogen carbonate solution, water and brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=3:2) to give the compound (1) (59 mg) and (2) (353mg) of the present invention having the following physical data.

EXAMPLE 24(1)

TLC:Rf 0.50 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.48 (m, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.22 (m, 1H), 6.94(m, 1H), 6.82 (m, 1H), 4.96 (dd, J=8.4, 4.2 Hz, 1H), 3.70-3.57 (m, 2H),2.63 (ddd, J=17.7, 5.4, 4.2 Hz, 1H), 2.53-2.38 (m, 2H), 2.09 (d, J=4.2Hz, 1H), 1.82-1.62 (m, 2H).

EXAMPLE 24(2)

TLC:Rf 0.42 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.44 (m, 1H), 7.40-7.32 (m, 2H), 7.19 (m, 1H), 6.80 (m,1H), 6.92 (m, 1H), 4.95 (dd, J=6.9, 4.5 Hz, 1H), 3.46 (t, J=11.4 Hz,1H), 3.13 (ddd, J=11.4, 5.4, 2.1 Hz, 1H), 2.73 (ddd, J=17.7, 5.4, 2.7Hz, 1H), 2.60-2.40 (m, 2H), 2.22 (m, 1H), 2.09 (d, J=4.5 Hz, 1H), 1.85(m, 1H).

EXAMPLES 25(1)˜25(4)

By the same procedure as described in Reference Example 20→ReferenceExample 21→Reference Example 22→Example 24 using the corresponding amidederivatives and aldehyde derivatives, the following compounds wereobtained.

EXAMPLE 25(1)

1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-((2,4-difluorophenyl)hydroxymethyl)piperidin-2-one

TLC:Rf 0.35 and 0.20 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.50 and 1.51 (s and s, 9H), 1.90-1.60 (m, 1H), 1.99 (m,1H), 2.56-2.10 (m, 3H), 3.07 (m, 1H), 3.42 (t, J=10.2 Hz, 1H), 3.60 (m,1H), 4.95 (m, 1H), 6.98-6.70 (m, 3H), 7.55-7.35 (m, 3H).

EXAMPLE 25(2) AND EXAMPLE 25(3)

1-(4-bromo-2,6-dichlorophenyl)-5-((2-thienyl)hydroxymethyl)piperidin-2-one

EXAMPLE 25(2)

TLC:Rf 0.52 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.76 (m, 2H) 2.28 (br. s., 1H) 2.54 (m, 3H) 3.58 (dd,J=11.90, 9.52 Hz, 1H) 3.70 (dd, J=11.90, 5.49 Hz, 1H) 4.90 (d, J=8.42Hz, 1H) 7.02 (m, 2H) 7.32 (d, J=4.94 Hz, 1H) 7.57 (m, 2H).

EXAMPLE 25(3)

TLC:Rf 0.35 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.88 (m, 1H) 2.35 (m, J=3.48, 1.46 Hz, 2H) 2.52 (m,J=17.76 Hz, 2 H) 2.69 (m, J=1.83 Hz, 1H) 3.17 (m, 1H) 3.32 (dd, J=11.53,10.44 Hz, 1H) 4.89 (d, J=7.69 Hz, 1H) 6.98 (m, 2H) 7.29 (m, 1H) 7.51 (m,2H).

EXAMPLE 25(4)

1-(4-bromo-2,6-dichlorophenyl)-5-((2,4-difluorophenyl)hydroxymethyl)piperidin-2-one

TLC:Rf 0.22 and 0.11 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 2.78-1.64 (m, 6H), 3.61-3.08 (m, 2H), 4.97 (m, 1H),6.98-6.77 (m, 2H), 7.60-7.40 (m, 3H).

REFERENCE EXAMPLE 23

4-((2,6-dichlorophenyl)aminocarbonyl)-2-(2-phenyl-1-hydroxyethyl)butanoicacid ethyl ester

By the same procedure as described in Reference Example 20 using2-phenylethanal instead of 2,4-difluorobenzaldehyde, the title compoundhaving the following physical data was obtained.

TLC:Rf 0.46 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.37 (d, J=8.1 Hz, 2H), 7.36-7.02 (m, 7H), 4.31-3.94 (m,3H), 2.94-2.10 (m, 8H), 1.38-1.20 (m, 3H).

REFERENCE EXAMPLE 24

4-((2,6-dichlorophenyl)aminocarbonyl)-2-(2-phenyl-1-((imidazol-1-yl)thioxomethoxy)ethyl)butanoicacid ethyl ester

To a solution of the compound prepared in Reference Example 23 (1.32 g)in dichloroethane (20 ml) was added 1,1′-thiocarbonyldiimidazole (1.22g) at room temperature. The reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with ethylacetate, washed with 2N hydrochloric acid and brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel (hexane:ethylacetate=1:1) to give the compound of the present invention (1.32 g)having the following physical data.

TLC:Rf 0.32 (hexane:ethyl acetate=3:2).

REFERENCE EXAMPLE 25

4-((2,6-dichlorophenyl)aminocarbonyl)-2-(2-phenylethyl)butanoic acidethyl ester

A solution of the compound prepared in Reference Example 24 (1.3 g),2,2′-azobis-isobutyronitrile (80 mg) and tributyltin hydride (1.29 ml)in toluene (20 ml) was stirred at 120° C. for 2 hours. The reactionmixture was concentrated, diluted with acetonitrile and washed withhexane, and the acetonitrile layer was concentrated. The obtainedresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=4:1) to give the compound of the present invention(867 mg) having the following physical data.

TLC:Rf 0.21 (hexane:ethyl acetate=4:1);

NMR (CDCl₃):d 7.36 (d, J=8.1 Hz, 2H), 7.33-7.14 (m, 6H), 7.04 (s, 1H),4.24-4.15 (m, 2H), 2.70-2.30 (m, 5H), 2.12-1.90 (m, 3H), 1.81 (m, 1H),1.38-1.20 (m, 3H).

EXAMPLE 26

1-(2,6-dichlorophenyl)-5-(2-phenylethyl)piperidin-2-one

By the same procedure as described in Reference Example 3→Example 2using the compound prepared in Reference Example 25, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.35 (toluene:ethyl acetate=4:1);

NMR (CDCl₃):d 7.43-7.36 (m, 2H), 7.35-7.16 (m, 6H), 3.48 (ddd, J=11.4,5.1, 1.8 Hz, 1H), 3.31 (dd, J=11.4, 9.9 Hz, 1H), 2.73-2.60 (m, 3H), 2.54(ddd, J=16.8, 10.8, 6.3 Hz, 1H), 2.18-2.00 (m, 2H), 1.81-1.62 (m, 3H).

REFERENCE EXAMPLE 26

4-(2,4-difluorophenylmethyl)-5-hydroxypentanoic acid ethyl ester

By the same procedure as described in Reference Example 5 using2-(2,4-difluorophenylmethyl)-4-ethoxycarbonylbutanoic acid, the titlecompound having the following physical data was obtained.

TLC:Rf 0.41 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.25 (t, J=7.14 Hz, 3H) 1.71 (m, 4H) 2.38 (m, 2H) 2.65 (m,2H) 3.50 (m, 2H) 4.13 (q, J=7.14 Hz, 2H) 6.80 (m, 2H) 7.14 (m, 1H).

REFERENCE EXAMPLE 27

4-(2,4-difluorophenylmethyl)-5-methylsulfonyloxypentanoic acid ethylester

To a solution of the compound prepared in Reference Example 26 (1 g) inpyridine (6 ml) was added methanesulfonyl chloride (0.76 ml) at 0° C.The reaction mixture was stirred at room temperature for 30 minutes. Thereaction mixture was poured in 1N hydrochloric acid and extracted witht-butyl methyl ether. The extract was washed with 1N hydrochloric acid,water and brine, dried over anhydrous sodium sulfate and concentrated togive the title compound (1.21 g) having the following physical data.

TLC:Rf 0.50 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.25 (t, J=7.14 Hz, 3H) 1.77 (m, 2H) 2.08 (m, 1H) 2.41 (m,2H) 2.71 (m, 2H) 3.01 (s, 3H) 4.10 (m, 4H) 6.82 (m, 2H) 7.16 (m, 1H).

REFERENCE EXAMPLE 28

4-(2,4-difluorophenylmethyl)-5-cyclohexylaminopentanoic acid ethyl ester

To a solution of cyclohexylamine (0.52 ml) in toluene (2 ml) was added asolution of the compound prepared in Reference Example 27 (150 mg) intoluene (1 ml). The reaction mixture was refluxed for 3.5 hours. Thereaction mixture was poured in 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumhydrogen carbonate solution, water and brine, dried over anhydroussodium sulfate and concentrated to give the title compound (120 mg)having the following physical data.

TLC:Rf 0.18 (ethyl acetate:methanol=10:1);

NMR (CDCl₃):d 1.03 (m, 2H) 1.24 (t, J=7.14 Hz, 3H) 1.41 (m, 2H) 1.71 (m,8H) 2.34 (m, 4H) 2.61 (m, 4H) 4.11 (q, J=7.14 Hz, 2H) 6.80 (m, 2H) 7.15(m, 1H).

EXAMPLE 27

1-cyclohexyl-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.25 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.06 (m, 1H) 1.36 (m, 5H) 1.62 (m, 3H) 1.79 (m, 3H) 2.02(m, 1 H) 2.32 (m, 1H) 2.48 (m, 1H) 2.63 (m, 2H) 2.87 (m, J=11.95, 9.75Hz, 1H) 3.21 (m, J=12.09, 4.67, 1.65 Hz, 1H) 4.46 (m, 1H) 6.82 (m, 2H)7.11 (m, 1H).

EXAMPLES 28(1) AND 28(2)

By the same procedure as described in Reference Example 28→Example 27using the corresponding amine derivatives instead of cyclohexylamine,the following compounds of the present invention were obtained.

EXAMPLE 28(1)

1-(2-(2-hydroxyethyl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.44 (ethyl acetate:methanol=10:1);

NMR (CDCl₃):d 1.73 (m, 1H) 2.01 (m, 1H) 2.33 (m, 1H) 2.63 (m, 7H) 3.41(m, 2 H) 3.87 (m, 2H) 6.82 (m, 2H) 7.10 (m, 2H) 7.36 (m, 3H).

EXAMPLE 28(2)

1-(3,5-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.60 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.99 (m, 1H) 2.28 (m, 1H) 2.51 (m, 1H) 2.66(m, 3 H) 3.45 (m, 2H) 6.83 (m, 2H) 7.11 (m, 1H) 7.16 (d, J=1.80 Hz, 2H)7.25 (t, J=1.80 Hz, 1H).

REFERENCE EXAMPLE 29

(2S)-4-benzyloxycarbonyl-2-(t-butoxycarbonylamino)butanoic acid2-(trimethylsilyloxy)ethyl esther

To a solution of(2S)-4-benzyloxycarbonyl-2-(t-butoxycarbonylamino)butanoic acid (5 g) indimethylformamide (3 ml) were added 2-(trimethylsilyl)ethanol (1.77 g),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (3.08 ml) anddimethylaminopyridine (183 mg) at room temperature. The reaction mixturewas stirred at room temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate/hexane, washed with 1N hydrochloric acid,water, a saturated aqueous sodium hydrogen carbonate solution, water andbrine, dried over anhydrous magnesium sulfate and concentrated to givethe title compound (1) (6.5 g) having the following physical data.

TLC:Rf 0.37 (hexane:ethyl acetate=4:1);

NMR (CDCl₃):d 0.04 (s, 9H) 1.00 (m, 2H) 1.43 (s, 9H) 1.98 (m, 1H) 2.21(m, 1H) 2.46 (m, 2H) 4.20 (m, 3H) 5.12 (s, 3H) 7.36 (m, 5H).

REFERENCE EXAMPLE 30

(2S,4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)-2-(t-butoxycarbonylamino)pentanoicacid 2-(trimethylsilyloxy)ethyl ester

By the same procedure as described in Reference Example 2 using lithiumbis(trimethylsilyl)amide and the compound prepared in Reference Example29 instead of lithium diisopropylamide, the title compound having thefollowing physical data was obtained.

TLC:Rf 0.43 (hexane:ethyl acetate=4:1);

NMR (CDCl₃):d 0.04 (s, 9H) 0.98 (m, 2H) 1.42 (s, 9H) 2.02 (m, 2H) 2.88(m, 3H) 4.17 (m, 2H) 4.38 (m, 1H) 4.95 (m, 2H) 5.05 (d, J=12.36 Hz, 1H)6.70 (m, 2H) 7.02 (m, 1H) 7.18 (m, 2H) 7.31 (m, 3H).

REFERENCE EXAMPLE 31

(2S,4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)-2-aminopentanoic acid2-(trimethylsilyloxy)ethyl ester

To the compound prepared in Reference Example 30 (1.3 g) was added asolution of 4N hydrochloric acid/ethyl acetate (5 ml). The reactionmixture was stirred at room temperature for 30 minutes. The reactionmixture was diluted with ethyl acetate, washed with a saturated aqueoussodium hydrogen carbonate solution, water and brine, dried overanhydrous magnesium sulfate and concentrated to give the title compoundhaving the following physical data.

TLC:Rf 0.27 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 0.04 (s, 9H) 0.97 (m, 2H) 1.87 (m, 2H) 2.90 (m, 3H) 3.43(m, 1 H) 4.17 (m, 2H) 5.02 (m, 2H) 6.73 (m, 2H) 7.03 (m, 1H) 7.21 (m,2H) 7.32 (m, 3 H).

REFERENCE EXAMPLE 32

(2S,4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)-2-carbonylaminopentanoicacid 2-(trimethylsilyloxy)ethyl ester

To a solution of the compound prepared in Reference Example 31 in formicacid (6.23 ml) was added acetic anhydride (1.95 ml) at 0° C. Thereaction mixture was stirred at room temperature for 30 minutes. Waterwas added to the reaction mixture, which was diluted with ethyl acetate.The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesiumsulfate and concentrated to give the title compound (1.15 g) having thefollowing physical data.

TLC:Rf 0.55 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 0.04 (s, 9H) 0.99 (m, 2H) 2.10 (m, 2H) 2.87 (m, 2H) 4.17(m, 3 H) 4.73 (m, 1H) 4.99 (s, 2H) 5.97 (d, J=8.24 Hz, 1H) 6.73 (m, 2H)7.03 (m, 1H) 7.21 (m, 2H) 7.35 (m, 3H) 8.02 (s, 1H).

REFERENCE EXAMPLE 33

(2S,4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)-2-isocyanidepentanoicacid 2-(trimethylsilyloxy)ethyl ester

To a solution of the compound prepared in Reference Example 32 (180 mg)in dichloromethane was added triethylamine (135 μl) and phosphorylchloride (87 mg) in dichloromethane (1 ml) at −78° C. The reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was poured in ice water and extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium hydrogen carbonatesolution, water and brine, dried over anhydrous magnesium sulfate andconcentrated to give the title compound having the following physicaldata.

TLC:Rf 0.55 (hexane:ethyl acetate=4:1);

NMR (CDCl₃):d 0.05 (s, 9H) 1.02 (m, 2H) 2.02 (m, 1H) 2.33 (m, 1H) 2.97(m, 3 H) 4.22 (m, 3H) 5.08 (m, 2H) 6.73 (m, 2H) 7.00 (m, 1H) 7.30 (m,5H).

REFERENCE EXAMPLE 34

(4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)pentanoic acid2-(trimethylsilyloxy)ethyl ester

To a solution of tributyltin hydride (148 mg) in toluene (20 ml) wereadded the compound prepared in Reference Example 33 and2,2′-azobis-isobutyronitrile (4 mg). The reaction mixture was stirred at100° C. for 30 minutes. The reaction mixture was concentrated. Theobtained residue was purified by column chromatography on silica gel(hexane:ethyl acetate=19:1→9:1) to give the compound of the presentinvention (132 mg) having the following physical data.

TLC:Rf 0.62 (hexane:ethyl acetate=4:1);

NMR (CDCl₃):d 0.03 (s, 9H) 0.95 (m, 2H) 1.92 (m, 2H) 2.29 (m, 2H) 2.81(m, 3 H) 4.14 (m, 2H) 5.04 (m, 2H) 6.72 (m, 2H) 7.03 (m, 1H) 7.21 (m,2H) 7.32 (m, 3 H).

REFERENCE EXAMPLE 35

(4S)-4-benzyloxycarbonyl-5-(2,4-difluorophenyl)pentanoic acid

By the same procedure as described in Reference Example 24 using thecompound prepared in Reference Example 34, the title compound having thefollowing physical data was obtained.

TLC:Rf 0.41 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.93 (m, 2H) 2.39 (m, 2H) 2.85 (m, 3H) 5.05 (m, 2H) 6.72(m, 2 H) 7.03 (m, 1H) 7.22 (m, 2H) 7.33 (m, 3H).

REFERENCE EXAMPLE 36

(2S)-4-(2,6-dichlorophenylaminocarbonyl)-2-(2,4-difluorophenylmethyl)butanoicacid benzyl ester

By the same procedure as described in Reference Example 1, using acidchloride which was made from the compound prepared in Reference Example35 and thionyl chloride, the title compound having the followingphysical data was obtained.

TLC:Rf 0.37 (hexane:ethyl acetate=7:3);

NMR (CDCl₃):d 2.02 (m, 2H) 2.37 (m, 2H) 2.89 (m, 3H) 5.10 (m, 2H) 6.75(m, 3 H) 7.05 (m, 1H) 7.19 (m, 1H) 7.31 (m, 7H).

EXAMPLE 29

(5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 3→Example 2using the compound prepared in Reference Example 36, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.34 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 1.73 (m, 1H) 1.98 (m, 1H) 2.38 (m, 1H) 2.52 (m, 1H) 2.68(m, 3 H) 3.36 (d, J=7.97 Hz, 2H) 6.82 (m, 2H) 7.17 (m, 2H) 7.38 (m, 2H).

EXAMPLE 30

(5S)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 29→ReferenceExample 30→Reference Example 31→Reference Example 32→Reference Example33→Reference Example 34→Reference Example 35→Reference Example36→Reference Example 3→Example 2 using(2R)-4-methoxycarbonyl-2-(t-butoxycarbonylamino)butanoic acid instead of(2S)-4-benzyloxycarbonyl-2-(t-butoxycarbonylamino)butanoic acid, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.34 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 1.71 (m, 1H) 1.97 (m, 1H) 2.37 (m, 1H) 2.51 (m, 1H) 2.67(m, 3 H) 3.35 (d, J=7.97 Hz, 2H) 6.81 (m, 2H) 7.17 (m, 2H) 7.37 (m, 2H).

REFERENCE EXAMPLE 37

By the same procedure as described in Reference Example 19 using(2R)-4-(methoxycarbonyl)-2-methylbutanoic acid and -2,4-difluorobenzylbromide, the title compound having the following physical data wasobtained.

TLC:Rf 0.40 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 1.19 (d, J=7.2 Hz, 3H), 1.50-1.61 (m, 1H), 2.10-2.20 (m,1H), 2.45-2.55 (m, 1H), 2.70-2.95 (m, 3H), 3.59 (s, 3H), 6.75-6.85 (m,2H), 7.05-7.15 (m, 1H).

EXAMPLE 31

(3R,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Reference Example 36→ReferenceExample 3→Example 2 using the compound prepared in Reference Example 37and 2,6-dichloroaniline, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.84 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.32 (m, 3H) 1.53 (m, 1H) 2.02 (m, 1H) 2.46 (m, 2H) 2.67(m, J=7.14 Hz, 2H) 3.35 (m, J=10.99 Hz, 2H) 6.82 (m, 2H) 7.19 (m,J=8.52, 7.42 Hz, 2 H) 7.36 (m, J=8.52 Hz, 2H).

EXAMPLES 31(1) AND 31(2)

By the same procedure as described in Reference Example 36→ReferenceExample 3→Example 2 using the compound prepared in Reference Example 37and the corresponding amine derivatives, the following compounds of thepresent invention were obtained.

EXAMPLE 31(1)

(3R,5R)-1-(4-nitro-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

TLC:Rf 0.70 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.30 (d, J=7.14 Hz, 3H) 1.54 (m, 1H) 2.05 (m, 1H) 2.55 (m,J=6.59 Hz, 2H) 2.69 (d, J=7.14 Hz, 2H) 3.32 (m, 2H) 6.83 (m, 2H) 7.12(m, J=8.10, 6.46 Hz, 1H) 8.25 (s, 2H).

EXAMPLE 31(2)

(3R,5R)-1-(4-bromo-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

TLC:Rf 0.41 (ethyl acetate:hexane=1:2);

NMR (CDCl₃):d 1.29 (d, J=6.87 Hz, 3H) 1.46 (m, 1H) 2.06 (m, J=7.14 Hz,1H) 2.07 (s, 3H) 2.15 (s, 3H) 2.32 (m, 1H) 2.51 (m, 1H) 2.65 (d, J=7.14Hz, 2H) 3.19 (m, J=11.26 Hz, 2H) 6.81 (m, 2H) 7.10 (m, 1H) 7.22 (s, 2H).

EXAMPLE 32

(3S,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-(benzyloxycarbonylamino)piperidin-2-one

TLC:Rf 0.28 (hexane:ethyl acetate=7:3);

NMR (CDCl₃):d 1.95 (m, 1H) 2.42 (m, 1H) 2.74 (m, 3H) 3.30 (dd, J=12.91,5.77 Hz, 1H) 3.58 (dd, J=12.91, 8.79 Hz, 1H) 4.54 (m, 1H) 5.14 (s, 2H)5.81 (m, 1H) 6.82 (m, 2H) 7.22 (m, 3H) 7.36 (m, 6H).

EXAMPLE 33

(3S,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-aminopiperidin-2-one

To a solution of the compound prepared in Example 32 (125 mg) inmethanol (5 ml) was added 10% palladium-carbon (36 mg). The reactionmixture was stirred for 10 minutes under an atmosphere of hydrogen. Thereaction mixture was filtrated through Celite (proprietary name) andconcentrated. The obtained residue was purified by preparative TLC(chloroform:methanol=9:1) to give the compound of the present invention(24 mg) having the following physical data.

TLC:Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.92 (m, 1H) 2.09 (m, 1H) 2.64 (m, 1H) 2.81 (m, 2H) 3.42(d, J=6.87 Hz, 2H) 3.71 (dd, J=7.69, 6.59 Hz, 1H) 6.82 (m, 2H) 7.20 (m,2H) 7.39 (m, 2H).

REFERENCE EXAMPLE 37

(4S)-4-(t-butoxycarbonylamino)-N-(2,6-dimethylphenyl)-5-((2-methoxyethoxy)methoxy)pentanamide

To a solution of(4S)-4-(t-butoxycarbonylamino)-5-((2-methoxyethoxy)methoxy)pentanoicacid (10 g) in N,N-dimethylformamide (30 ml) were added2,6-dimethylaniline (4.5 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (27 g),1-hydroxybenzotriazole (18 g) and triethylamine (18 ml). The reactionmixture was stirred at room temperature overnight. Water was added tothe reaction mixture, which was extracted with ethyl acetate. Ethylacetate layer was washed with brine, dried over anhydrous sodium sulfateand concentrated to give the compound of the present invention (11 g)having the following physical data.

TLC:Rf 0.53 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.45 (s, 9H) 1.96 (m, 2H) 2.24 (s, 6H) 2.48 (m, 2H) 3.39(s, 3H) 3.65 (m, 6H) 3.94 (m, 1H) 4.72 (s, 2H) 5.13 (m, 1H) 7.10 (m, 3H)8.06 (s, 1H).

REFERENCE EXAMPLE 38

(4S)-4-amino-N-(2,6-dimethylphenyl)-5-hydroxypentanamide

By the same procedure as described in Reference Example 31 using thecompound prepared in Reference Example 37, the title compound having thefollowing physical data was obtained.

TLC:Rf 0.27 (ethyl acetate:methanol:28% aqueous ammoniasolution=16:3:1);

NMR (DMSO-d₆):d 2.15-2.30 (m, 1H) 2.45-2.60 (m, 1H) 3.10-3.30 (m, 2H)3.40-3.50 (m, 1H) 3.95-4.20 (m, 2H) 5.40 (br, s, 1H) 7.84 (s, 3H) 10.05(s, 1H).

REFERENCE EXAMPLE 39

(4S)-4-(t-butoxycarboxyamino)-N-(2,6-dimethylphenyl)-5-hydroxypentanamide

To a suspension of the compound prepared in Reference Example 38 (200mg) in t-butanol (2 ml) were added di-t-butyldicarbonate (1 ml),catalytic amount of N,N-dimethylaminopyridine and the reaction mixturewas stirred at room temperature for 2.5 hours. Water was added to thereaction mixture, which was extracted with ethyl acetate. Ethyl acetatelayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated to give the compound of the present invention (200 mg)having the following physical data.

TLC:Rf 0.63 (ethyl acetate:methanol: 28% aqueous ammoniasolution=8:1:1);

NMR (CDCl₃):d 1.53 (s, 9H) 1.80-2.05 (m, 2H) 2.22 (s, 6H) 2.53 (m, 2H)2.84 (m, 1H) 3.59-3.80 (m, 3H) 5.14 (m, 1H) 7.02-7.20 (m, 3H) 7.61 (s,1H).

REFERENCE EXAMPLE 40

(5S)-1-(2,6-dimethylphenyl)-5-aminopiperidin-2-one

By the same procedure as described in Reference Example 27→Example 1using the compound prepared in Reference Example 39, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.41 (ethyl acetate:methanol:28% aqueous ammonia solution=8:1:1);

NMR (DMSO-d₆):d 2.08 (s, 3H) 2.16 (s, 3H) 2.47 (m, 3H) 3.07 (m, 1H) 3.61(m, 2 H) 4.11 (m, 1H) 7.16 (m, 3H) 8.07 (m, 2H).

EXAMPLE 34

(5S)-1-(2,6-dimethylphenyl)-5-(2,4-difluorophenylsulfonylamino)piperidin-2-one

TLC:Rf 0.60 (ethyl acetate);

NMR (CDCl₃):d 2.03 (m, 1H) 2.15 (s, 3H) 2.18 (s, 3H) 2.53 (m, 3H) 3.04(m, 2H) 4.10 (m, J=14.28, 7.14 Hz, 1H) 4.45 (m, J=1.10 Hz, 1H) 6.95 (m,2H) 7.16 (m, 3H) 7.79 (m, 1H).

EXAMPLE 35

1-(4-(3-ethoxycarbonylpropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1 using thecompound prepared in Example 10(1), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.54 (acetone:hexane=1:1);

NMR (CDCl₃):d 8.95-8.90 (m, 1H), 7.44-7.32 (m, 2H), 7.18-7.07 (m, 1H),6.87-6.75 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.32-3.25 (m, 2H), 2.75-2.65(m, 3H), 2.62-2.47 (m, 1H), 2.42-2.27 (m, 5H), 2.07-1.89 (m, 3H),1.80-1.65 (m, 1H), 1.26 (t, J=7.2 Hz, 3H).

EXAMPLE 36

1-(4-(3-carboxypropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 35 (114 mg) in ethanol(2.2 ml) was added a 5N aqueous sodium hydroxide solution (0.26 ml). Thereaction mixture was stirred at room temperature for 2.5 hours. Waterwas added to the reaction mixture, which was extracted with t-butylmethyl ether. The water layer was acidified with 1N hydrochloric acidand the reaction mixture was extracted with ethyl acetate. The ethylacetate layer was washed with brine, dried over anhydrous sodium sulfateand concentrated to give the compound of the present invention (88 mg)having the following physical data.

TLC:Rf 0.39 (ethyl acetate:methanol=5:1);

NMR (DMSO-d₆):d 12.13-11.80 (m, 1H), 10.26 (s, 1H), 7.73 (s, 2H),7.45-7.33 (m, 1H), 7.23-7.10 (m, 1H), 7.07-6.96 (m, 1H), 3.30-3.14 (m,2H), 2.70 (d, J=6.9 Hz, 2H), 2.50-2.17 (m, 7H), 1.92-1.72 (m, 3H),1.68-1.48 (m, 1H).

EXAMPLE 37

1-(4-(4-hydroxybutylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 5 using thecompound prepared in Example 36, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.51 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 9.07 (brs, 1H), 7.37 and 7.31 (each d, J=2.1 Hz, each 1H),7.18-7.08 (m, 1H), 6.88-6.74 (m, 2H), 3.70-3.60 (m, 2H), 3.35-3.25 (m,2H), 2.80-2.48 (m, 4H), 2.44-2.23 (m, 3H), 2.07-1.93 (m, 2H), 1.82-1.67(m, 4H).

EXAMPLE 38

1-(4-(2-(ethoxycarbonyl)ethylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1 using thecompound prepared in Example 10(1) and 3-chlorocarbonylpropanoic acidethyl ester, the compound of the present invention having the followingphysical data was obtained.

TLC:Rf 0.46 (acetone:hexane=1:1);

NMR (CDCl₃):d 9.14 (brs, 1H), 7.38 and 7.33 (each d, J=2.4 Hz, each 1H),7.33-7.17 (m, 1H), 6.87-6.74 (m, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.34-3.25(m, 2H), 2.80-2.47 (m, 8H), 2.45-2.28 (m, 1H), 2.07-1.93 (m, 1H),1.80-1.67 (m, 1H), 1.26 (t, J=7.2 Hz, 3H).

EXAMPLE 39

1-(4-(2-carboxyethylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 38, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.38 (ethyl acetate:methanol:water=7:2:1);

NMR (DMSO-d₆):d 12.32-12.00 (m, 1H), 10.36 (s, 1H), 7.73 and 7.72 (eachs, each 1H), 7.46-7.34 (m, 1H), 7.26-7.13 (m, 1H), 7.06-6.97 (m, 1H),3.30-3.13 (m, 2H), 2.70 (d, J=6.3 Hz, 2H), 2.66-2.37 (m, 6H), 2.34-2.18(m, 1H), 1.92-1.79 (m, 1H), 1.70-1.50 (m, 1H).

EXAMPLE 40

1-(4-(3-hydroxypropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 37 using the compoundprepared in Example 39, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.55 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 9.17 (s, 1H), 7.38-7.30 (m, 2H), 7.18-7.08 (m, 1H),6.88-6.74 (m, 2H), 3.72-3.61 (m, 2H), 3.37-3.25 (m, 2H), 3.02-2.91 (m,1H), 2.80-2.49 (m, 4H), 2.46-2.28 (m, 3H), 2.08-1.65 (m, 4H).

EXAMPLE 41

1-(4-methanesulfonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 10(1) (124 mg) indichloromethane (3.2 ml) were added pyridine (0.13 ml) andmethanesulfonyl chloride (0.026 ml) at 0° C. The reaction mixture wasstirred at room temperature for 1 hour. 1N hydrochloric acid was addedto the reaction mixture, which was extracted with t-butyl methyl ether.The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfateand concentrated. The obtained residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:3→1:3) to give thecompound of the present invention (121 mg) having the following physicaldata.

TLC:Rf 0.32 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 8.26-8.12 (m, 1H), 7.19-7.02 (m, 3H), 6.78-6.73 (m, 2H),3.35-3.25 (m, 2H), 3.00 (s, 3H), 2.79-2.49 (m, 4H), 2.46-2.28 (m, 1H),2.07-1.93 (m, 1H), 1.80-1.64 (m, 1H).

EXAMPLE 42

1-(2,6-dichloro-4-(pyrrolidin-2,5-dion-1-yl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 10(1) (76 mg) intoluene (4 ml) was added 3,5-dihydrofuran-2,5-dione (21 mg). Thereaction mixture was refluxed for 2 hours. The reaction mixture wasconcentrated. To the obtained residue was added acetyl chloride (5 ml).The reaction mixture was refluxed for 45 minutes. The reaction mixturewas concentrated. The obtained residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:3→0:1) to give thecompound of the present invention (61 mg) having the following physicaldata.

TLC:Rf 0.40 (ethyl acetate);

NMR (CDCl₃):d 7.47-7.40 (m, 2H), 7.20-7.10 (m, 1H), 6.88-6.73 (m, 2H),3.35-3.28 (m, 2H), 2.90 (s, 4H), 2.79-2.65 (m, 3H), 2.60-2.47 (m, 1H),2.45-2.28 (m, 1H), 2.08-1.93 (m, 1H), 1.80-1.65 (m, 1H).

EXAMPLE 43

1-(2,6-dichloro-4-(piperidin-2,6-dion-1-yl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 42 using3,4,5-trihydropyran-2,6-dione instead of 3,5-dihydrofuran-2,5-dione, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.32 (ethyl acetate);

NMR (CDCl₃):d 7.20-7.10 (m, 3H), 6.88-6.76 (m, 2H), 3.34 (d, J=7.8 Hz,2H), 2.81 (t, J=6.6 Hz, 4H), 2.75-2.65 (m, 3H), 2.60-2.27 (m, 2H),2.13-1.93 (m, 3H), 1.80-1.67 (m, 1H).

EXAMPLE 44

1-(4-t-butylcarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1 using thecompound prepared in Example 10(1) and pivaloyl chloride, the compoundof the present invention having the following physical data wasobtained.

TLC:Rf 0.46 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.25 (m, 9H) 1.74 (m, 2H) 1.97 (m, 1H) 2.33 (m, 1H) 2.51(m, 1 H) 2.68 (m, 2H) 3.29 (m, 2H) 6.80 (m, 2H) 7.14 (m, 1H) 7.46 (d,J=2.20 Hz, 1H) 7.53 (d, J=2.20 Hz, 1H) 8.33 (s, 1H).

EXAMPLE 45

1-(4-methoxycarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1 using thecompound prepared in Example 10(1) and methyl chloroformate, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.36 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.75 (m, 1H) 1.99 (m, 1H) 2.36 (m, 1H) 2.55 (m, 1H) 2.70(m, 3 H) 3.31 (d, J=7.69 Hz, 2H) 3.72 (s, 3H) 6.82 (m, 2H) 7.13 (m, 1H)7.13 (m, J=6.59 Hz, 1H) 7.27 (m, 1H) 7.33 (d, J=2.20 Hz, 1H) 8.19 (s,1H).

EXAMPLE 46

1-(4-(N,N-diethylamino)methylcarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 1→ReferenceExample 17 using the compound prepared in Example 10(1) and chloroacetylchloride, the compound of the present invention having the followingphysical data was obtained.

TLC:Rf 0.33 (ethyl acetate:methanol=10:1);

NMR (CDCl₃):d 1.08 (t, J=7.14 Hz, 6H) 1.72 (m, 1H) 1.95 (m, 1H) 2.35 (m,1H) 2.51 (m, 1H) 2.67 (m, 7H) 3.15 (s, 2H) 3.33 (m, 2H) 6.82 (m, 2H)7.14 (m, 1H) 7.68 (m, 2H) 9.55 (m, 1H).

EXAMPLE 47

1-((4-(1-methylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 10(1) (100 mg) indichloroethane (2 ml) were added 1-methylpiperidin-4-one (44 mg), aceticacid (75 μl) and sodium triacetoxyborohydride (165 mg) to roomtemperature for 24 hours. Ethyl acetate was added to the reactionmixture, which was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by preparative TLC(chloroform:methanol=9:1) to give the compound of the present invention(19 mg) having the following physical data.

TLC:Rf 0.38 (chloroform:methanol=4:1);

NMR (CDCl₃):d 1.50 (m, 2H) 1.66 (m, 1H) 1.97 (m, 3H) 2.14 (m, 2H) 2.34(m, 4 H) 2.49 (m, 1H) 2.65 (m, 3H) 2.80 (m, 2H) 3.19 (m, 1H) 3.31 (d,J=7.97 Hz, 2H) 3.79 (d, J=7.42 Hz, 1H) 6.53 (m, 2H) 6.81 (m, 2H) 7.15(m, 1H).

EXAMPLES 47(1)˜(4)

By the same procedure as described in Example 47 using the correspondingketone or aldehyde derivatives instead of 1-methylpiperidin-4-one, thefollowing compounds of the present invention were obtained.

EXAMPLE 47(1)

1-(4-((1-acetylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.27 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.33 (m, 2H) 1.69 (m, 1H) 2.00 (m, 6H) 2.33 (m, 1H) 2.49(m, 1 H) 2.66 (m, 3H) 2.86 (m, 1H) 3.21 (m, 1H) 3.38 (m, 3H) 3.79 (m,1H) 3.98 (d, J=7.69 Hz, 1H) 4.45 (m, 1H) 6.52 (m, 2H) 6.81 (m, 2H) 7.14(m, 1H).

EXAMPLE 47(2)

1-(4-(2-hydroxybenzyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.60 (ethyl acetate:hexane=7:3);

NMR (CDCl₃):d 1.67 (m, 1H) 1.96 (m, 1H) 2.33 (m, 1H) 2.50 (m, 1H) 2.67(m, 3 H) 3.30 (t, J=5.95 Hz, 2H) 4.17 (d, J=5.68 Hz, 2H) 4.63 (t, J=5.68Hz, 1H) 6.60 (m, 2H) 6.82 (m, 4H) 7.14 (m, 3H) 7.41 (s, 1H).

EXAMPLE 47(3)

1-(4-((2-methylimidazol-4-yl)methylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.28 (dichloromethane:methanol=4:1);

NMR (CDCl₃):d 1.71 (m, 1H) 1.97 (m, 1H) 2.33 (m, 4H) 2.51 (m, 1H) 2.67(m, 3 H) 3.32 (d, J=7.69 Hz, 2H) 4.03 (d, J=5.13 Hz, 2H) 4.70 (m, 1H)6.41 (m, 3H) 6.81 (m, 2H)7.14 (m, 1H)10.11 (m, 1H).

EXAMPLE 47(4)

1-(4-((1-t-butoxycarbonylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.55 (ethyl acetate:hexane=7:3);

NMR (CDCl₃):d 1.32 (m, 2H) 1.47 (s, 9H) 1.68 (m, 1H) 1.96 (m, 3H) 2.33(m, 1 H) 2.52 (m, 1H) 2.66 (m, 3H) 2.92 (m, 2H) 3.31 (m, 3H) 3.77 (d,J=7.87 Hz, 1H) 4.03 (m, 2H) 6.54 (m, 2H) 6.82 (m, 2H) 7.14 (m, 1H).

EXAMPLE 48

1-(4-(piperidin-4-ylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 47(4) (193 mg) indichloromethane (1 ml) and water (0.1 ml) was added trifluoroacetic acid(1 ml) at 0° C. The reaction mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated, dissolved in t-butylmethyl ether/tetrahydrofuran, washed with a 1N sodium hydroxide solutionand brine, dried over anhydrous magnesium sulfate and concentrated togive the compound of the present invention (159 mg) having the followingphysical data.

TLC:Rf 0.13 (chloroform:methanol:aqueous ammonia solution=90:10:1);

NMR (CDCl₃):d 1.39 (m, 2H) 1.68 (m, 1H) 1.97 (m, 3H) 2.33 (m, 1H) 2.52(m, 2 H) 2.68 (m, 5H)3.16 (m, 2H)3.29 (m, 3H)3.92 (d, J=7.87 Hz, 1H)6.53(m, 2H) 6.81 (m, 2H) 7.14 (m, 1H).

EXAMPLE 49

1-(4-(1-methanesulfonylpiperidin-4-ylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 41 using the compoundprepared in Example 48, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.26 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 1.62 (m, 3H) 1.95 (m, 1H) 2.11 (m, 2H) 2.33 (m, 1H) 2.49(m, 1 H) 2.66 (m, 3H) 2.81 (s, 3H) 2.90 (m, 2H) 3.31 (m, 3H) 3.74 (m,2H) 3.92 (d, J=7.69 Hz, 1H) 6.53 (m, 2H) 6.82 (m, 2H) 7.15 (m, 1H).

EXAMPLE 50

1-(4-ethylaminocarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 13 using thecompound prepared in Example 10(1) and ethyl isocyanate, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.25 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 1.10 (t, J=7.28 Hz, 3H) 1.73 (m, 1H) 1.99 (m, 1H) 2.35 (m,1H) 2.53 (m, 1H) 2.69 (m, 3H) 3.19 (m, 2H) 3.35 (d, J=7.69 Hz, 2H) 5.25(t, J=5.36 Hz, 1H) 6.83 (m, 2H)7.15 (m, 3H)7.78 (s, 1H).

EXAMPLE 51

1-(4-(N,N-dimethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 13 using the compoundprepared in Example 10(1), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.57 (ethyl acetate);

NMR (CDCl₃):d 1.69 (m, 1H) 1.95 (m, 1H) 2.34 (m, 1H) 2.50 (m, 1H) 2.67(m, 3 H) 2.94 (s, 6H) 3.33 (d, J=8.00 Hz, 2H) 6.64 (m, 2H) 6.81 (m, 2H)7.15 (m, 1H).

EXAMPLE 52

1-(4-((2S)-2-(t-butoxycarbonylamino)-3-benzyloxypropanoylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 37 using thecompound prepared in Example 10(1) andN-(t-butoxycarbonyl)-O-benzyl-L-serine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.34 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 9.27-9.17 (m, 1H), 7.73-7.22 (m, 6H), 7.20-7.04 (m, 2H),6.88-6.74 (m, 2H), 5.64-5.50 (m, 1H), 4.60-4.38 (m, 3H), 3.91-3.60 (m,2H), 3.34-3.25 (m, 2H), 2.78-2.63 (m, 3H), 2.62-2.47 (m, 1H), 2.43-2.26(m, 1H), 2.05-1.82 (m, 1H), 1.80-1.60 (m, 1H), 1.51-1.40 and 0.98-0.91(each m, totally 9H).

EXAMPLE 53

1-(4-((2S)-2-(t-butoxycarbonylamino)-3-hydroxypropanoylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 52, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.29 (ethyl acetate);

NMR (CDCl₃):d 9.37-9.24 (m, 1H), 7.73-7.68 (m, 1H), 7.46-7.08 (m, 3H),6.88-6.74 (m, 2H), 5.70-5.58 (m, 1H), 4.08-3.60 (m, 3H), 3.40-3.20 (m,2H), 2.80-2.25 (m, 5H), 2.07-1.87 (m, 1H), 1.80-1.57 (m, 1H), 1.53-1.40(m, 9H).

EXAMPLE 54

1-(4-(L-serylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 48 using the compoundprepared in Example 53, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.18 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.71 (m, 1H) 2.23 (m, 6H) 2.64 (m, 1H) 2.72 (m, 2H) 3.32(m, 2 H) 3.60 (m, 1H) 3.80 (m, 1H) 3.93 (m, 1H) 6.81 (m, 2H) 7.14 (m,1H) 7.58 (s, 1 H)7.71 (s, 1H)9.70 (m, 1H).

EXAMPLE 55

1-(4-(L-tyrosylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 52→Example 53→Example 54using N-(t-butoxycarbonyl)-O-benzyl-L-tyrosine instead ofN-(t-butoxycarbonyl)-O-benzyl-L-serine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.51 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.82 (m, 5H) 2.36 (m, 1H) 2.53 (m, 1H) 2.72 (m, 4H) 3.14(dd, J=13.70, 4.20 Hz, 1H) 3.35 (m, 2H) 3.66 (dd, J=8.60, 4.20 Hz, 1H)6.70 (d, J=8.40 Hz, 2H) 6.82 (m, 2H) 7.01 (d, J=8.40 Hz, 2H) 7.14 (m,1H) 7.52 (m, 1H) 7.74 (m, 1H) 9.56 (m, 1H).

EXAMPLE 56

1-(4-(L-asparaginylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 52→Example 53→Example 54using N-(t-butoxycarbonyl)-L-asparagine instead ofN-(t-butoxycarbonyl)-O-benzyl-L-serine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.22 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.82 (m, 4H) 2.34 (m, 1H) 2.51 (m, 1H) 2.69 (m, 5H) 3.32(m, 2 H) 3.76 (t, J=6.00 Hz, 1H) 5.42 (m, 1H) 5.99 (m, 1H) 6.82 (m, 2H)7.14 (m, 1H) 7.62 (s, 1H) 7.69 (s, 1H) 9.77 (m, 1H).

EXAMPLE 57

1-(4-(N-(pyridin-2-ylmethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 13 using the compoundprepared in Example 16(10) and 2-bromomethylpyridine, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.26 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.37 (s, 9H) 1.70 (m, 1H) 1.97 (m, 1H) 2.35 (m, 1H) 2.50(m, 1 H) 2.69 (m, 3H) 3.30 (d, J=8.24 Hz, 2H) 4.90 (s, 2H) 6.82 (m, 2H)7.19 (m, 3H) 7.46 (m, 2H) 7.69 (m, 1H) 8.58 (m, 1H).

EXAMPLE 58

1-(4-(pyridin-2-ylmethylamino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one

TLC:Rf 0.34 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 1.69 (m, 1H) 1.92 (m, 1H) 2.32 (m, 1H) 2.49 (m, 1H) 2.66(m, 3 H) 3.32 (d, J=7.97 Hz, 2H) 4.37 (d, J=4.94 Hz, 2H) 5.29 (t, J=5.22Hz, 1H) 6.63 (m, 2H) 6.81 (m, 2H) 7.20 (m, 3H) 7.67 (td, J=7.69, 1.92Hz, 1H) 8.58 (m, 1H).

EXAMPLE 59

1-(4-(N-ethoxycarbonylmethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 13 using the compoundprepared in Example 16(10) and ethyl 2-bromoacetate, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.38 (ethyl acetate);

NMR (CDCl₃):d 7.36 (s, 2H), 7.20-7.08 (m, 1H), 6.89-6.75 (m, 2H),4.33-4.19 (m, 4H), 3.38-3.26 (m, 2H), 2.80-2.30 (m, 5H), 2.07-1.93 (m,1H), 1.80-1.63 (m, 1H), 1.47 (s, 9H), 1.38-1.22 (m, 3H).

EXAMPLE 60

1-(4-ethoxycarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 59, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.35 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.31 (t, J=7.14 Hz, 3H) 1.69 (m, 1H) 1.95 (m, 1H) 2.33 (m,1H) 2.49 (m, 1H) 2.66 (m, 3H) 3.31 (d, J=7.69 Hz, 2H) 3.83 (d, J=5.22Hz, 2H) 4.26 (q, J=7.14 Hz, 2H) 4.55 (t, J=4.94 Hz, 1H) 6.56 (s, 2H)6.81 (m, 2H) 7.14 (m, 1H).

EXAMPLE 61

1-(4-carboxymethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 60, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.16 (ethyl acetate:methanol=3:1);

NMR (DMSO-d₆):d 1.57 (m, 1H) 1.84 (m, 1H) 2.24 (m, 1H) 2.39 (m, 2H) 2.69(m, 2H) 3.18 (m, 2H) 3.85 (m, 2H) 6.55 (m, 1H) 6.66 (s, 2H) 7.02 (m, 1H)7.18 (m, 4 H) 7.38 (m, 1H) 12.68 (m, 1H).

EXAMPLE 62

1-(4-(N-carboxymethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 59, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.18 (ethyl acetate);

NMR (CDCl₃):d 1.45 (s, 9H) 1.72 (m, 1H) 2.00 (m, 1H) 2.36 (m, 1H) 2.55(m, 1 H) 2.71 (m, 3H) 3.33 (d, J=7.97 Hz, 2H) 4.19 (s, 2H) 6.82 (m, 2H)7.14 (m, 1H) 7.37 (m, 2H).

EXAMPLE 63

1-(4-(N-(2-hydroxyethyl)-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 59 (3.28 g) indimethylformamide (20 ml) were added N-hydroxysuccinimide (1.53 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.08 g) at roomtemperature for 1 hour. The reaction mixture was poured in water andextracted with ethyl acetate and hexane (1:1). The extract was washedwith brine, dried over anhydrous magnesium sulfate and concentrated. Toa solution of the obtained residue in tetrahydrofuran (20 ml) were addedsodium borohydride (447 mg) and water (870 μl) at 0° C. The reactionmixture was stirred at room temperature for 30 minutes. 1N hydrochloricacid was added to the reaction mixture, which was extracted with ethylacetate. The extracted was washed with a saturated aqueous sodiumhydrogen carbonate solution and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was washed with isopropylether/hexane to give the compound of the present invention (2.08 g)having the following physical data.

TLC:Rf 0.37 (hexane:ethyl acetate=1:4);

NMR (CDCl₃):d 1.47 (s, 9H) 1.71 (m, 1H) 1.99 (m, 1H) 2.17 (m, 1H) 2.36(m, 1 H) 2.51 (m, 1H) 2.68 (m, 3H) 3.33 (d, J=7.69 Hz, 2H) 3.79 (m, 4H)6.83 (m, 2H) 7.15 (m, 1H) 7.35 (m, 2H).

EXAMPLE 64

1-(4-(2-hydroxyethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 63, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.28 (ethyl acetate);

NMR (CDCl₃):d 1.69 (m, 1H) 1.95 (m, 1H) 2.10 (t, J=5.49 Hz, 1H) 2.33 (m,1H) 2.49 (m, 1H) 2.66 (m, 3H) 3.17 (q, J=5.49 Hz, 2H) 3.33 (d, J=7.97Hz, 2H) 3.78 (m, 2H) 4.44 (t, J=5.49 Hz, 1H) 6.53 (s, 2H) 6.81 (m, 2H)7.15 (m, 1H).

EXAMPLE 65

1-(4-(N-aminocarbonylmethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 59 (395 mg) indimethylformamide (5 ml) were added N-hydroxysuccinimide (168 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (228 mg). The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas poured in water and extracted with ethyl acetate and hexane (1:1).The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. To a solution of the obtained residue intetrahydrofuran (10 ml) was added aqueous ammonia solution (5.0 ml). Thereaction mixture was stirred at room temperature for 15 minutes. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:9→0:1) to give the compound of the presentinvention (348 mg) having the following physical data.

TLC:Rf 0.22 (hexane:ethyl acetate=1:9);

NMR (CDCl₃):d 1.48 (s, 9H) 1.70 (m, 1H) 1.98 (m, 1H) 2.35 (m, 1H) 2.51(m, 1 H) 2.69 (m, 3H) 3.32 (d, J=7.97 Hz, 2H) 4.17 (s, 2H) 5.46 (br. s.,1H) 5.91 (br. s., 1 H) 6.83 (m, 2H) 7.14 (m, 1H) 7.40 (m, 2H).

EXAMPLE 66

1-(4-aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 48 using the compoundprepared in Example 65, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.39 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.97 (m, 1H) 2.35 (m, 1H) 2.50 (m, 1H) 2.66(m, 3 H) 3.32 (d, J=7.69 Hz, 2H) 3.47 (d, J=5.22 Hz, 2H) 5.26 (t, J=5.22Hz, 1H) 5.40 (m, 1H)6.44 (s, 2H)6.66 (m, 1H)6.82 (m, 2H)7.14 (m, 1H).

EXAMPLE 67

1-(4-(N,N-dimethylamino)carbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 37→Example 48using the compound prepared in Example 59 and dimethylamine, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.29 (ethyl acetate);

NMR (CDCl₃):d 1.68 (m, 1H) 1.95 (m, 1H) 2.34 (m, 1H) 2.49 (m, 1H) 2.66(m, 3 H) 3.03 (s, 3H) 3.04 (s, 3H) 3.33 (d, J=7.69 Hz, 2H) 3.78 (d,J=4.12 Hz, 2H) 5.19 (m, 1H)6.58 (m, 2H)6.82 (m, 2H)7.15 (m, 1H).

EXAMPLES 67(1)˜67(8)

By the same procedure as described in Example 67 using the correspondingamine derivatives instead of dimethylamine, the following compounds ofthe present invention were obtained.

EXAMPLE 67(1)

1-(4-methylaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.38 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.69 (m, 1H) 1.97 (m, 1H) 2.34 (m, 1H) 2.50 (m, 1H) 2.66(m, 3 H) 2.81 (d, J=4.94 Hz, 3H) 3.32 (d, J=7.69 Hz, 2H) 3.56 (d, J=5.49Hz, 2H) 5.01 (t, J=5.49 Hz, 1H) 6.47 (s, 2H) 6.54 (m, 1H) 6.82 (m, 2H)7.15 (m, 1H).

EXAMPLE 67(2)

1-(4-(4-methylpiperazin-1-ylcarbonylmethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.34 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.95 (m, 1H) 2.31 (m, 4H) 2.44 (m, 5H) 2.66(m, 3 H) 3.32 (d, J=7.97 Hz, 2H) 3.45 (m, 2H) 3.68 (m, 2H) 3.80 (d,J=3.85 Hz, 2H) 5.20 (t, J=3.85 Hz, 1H) 6.58 (m, 2H) 6.82 (m, 2H) 7.15(m, 1H).

EXAMPLE 67(3)

1-(4-(N,N-dimethylamino)aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.45 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.95 (m, 1H) 2.33 (m, 1H) 2.49 (m, 7H) 2.69(m, 3 H) 3.32 (m, 2H) 3.42 and 3.95 (d, J=5.22 Hz, and d, J=4.40 Hz, 1H)4.94 and 5.07 (t, J=4.40 Hz, and m, 1H) 6.22 and 7.49 (s and s, 1H) 6.45and 6.60 (s and m, 2H) 6.82 (m, 2H) 7.15 (m, 1H).

EXAMPLE 67(4)

1-(4-aminoaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.34 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.68 (m, 1H) 1.97 (m, 1H) 2.34 (m, 1H) 2.50 (m, 1H) 2.65(m, 3 H) 3.32 (d, J=7.69 Hz, 2H) 3.53 (d, J=5.49 Hz, 2H) 3.82 (m, 2H)5.18 (m, 1H) 6.46 (m, 2H) 6.83 (m, 2H) 7.14 (m, 1H) 7.89 (br. s., 1H).

EXAMPLE 67(5)

1-(4-(2-hydroxyethylamino)carbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.25 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.65 (m, 1H) 1.97 (m, 1H) 2.33 (m, 1H) 2.51 (m, 1H) 2.66(m, 3 H) 3.18 (m, 1H) 3.33 (d, J=7.51 Hz, 2H) 3.39 (m, 2H) 3.50 (d,J=5.49 Hz, 2H) 3.64 (m, 2H) 5.10 (m, 1H) 6.48 (s, 2H) 6.82 (m, 2H) 7.06(m, 1H) 7.14 (m, 1H).

EXAMPLE 67(6)

1-(4-t-butylaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.36 (ethyl acetate);

NMR (CDCl₃):d 1.31 (s, 9H) 1.71 (m, 1H) 1.96 (m, 1H) 2.35 (m, 1H) 2.50(m, 1 H) 2.67 (m, 3H) 3.34 (m, 4H) 5.11 (m, 1H) 6.42 (m, 3H) 6.82 (m,2H) 7.14 (m, 1 H).

EXAMPLE 67(7)

1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.29 (dichloromethane:methanol=4:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.93 (m, 1H) 2.17 (s, 6H) 2.35 (m, 3H) 2.49(m, 1 H) 2.66 (m, 3H) 3.33 (m, 4H) 3.62 (d, J=5.13 Hz, 2H) 5.02 (t,J=5.22 Hz, 1H) 6.49 (m, 2H)6.81 (m, 3H)7.14 (m, 1H).

EXAMPLE 67(8)

1-(4-benzyloxyaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.26 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.95 (m, 1H) 2.47 (m, 3H) 2.71 (d, J=7.14 Hz,2H) 3.31 (d, J=7.69 Hz, 2H) 3.44 (m, 2H) 4.91 (m, 3H) 6.41 (m, 2H) 6.82(m, 2H) 7.14 (m, 1H) 7.37 (m, 5H) 9.43 (br. s., 1H).

EXAMPLE 68

1-(4-hydroxyaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 67(8), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.29 (chloroform:methanol=9:1);

NMR (DMSO-d₆):d 1.56 (m, 1H) 1.85 (m, 1H) 2.27 (m, 3H) 2.69 (d, J=7.14Hz, 2 H) 3.28 (m, 2H) 3.60 (d, J=6.04 Hz, 2H) 6.66 (m, 3H) 7.02 (m, 1H)7.18 (m, 1H) 7.37 (m, 1H) 8.91 (br. s., 1H) 10.59 (br. s., 1H).

EXAMPLE 69

1-(4-(3-(N,N-dimethylamino)propyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 13→ReferenceExample 15→Reference Example 27→Reference Example 28→Example 48 usingthe compound prepared in Example 16(10) and 3-bromo-1-benzyloxypropane,the compound of the present invention having the following physical datawas obtained.

TLC:Rf 0.13 (chloroform:methanol=4:1);

NMR (CDCl₃):d 1.71 (m, 3H) 1.94 (m, 1H) 2.24 (s, 6H) 2.35 (m, 3H) 2.49(m, 1 H) 2.66 (m, 3H) 3.12 (m, 2H) 3.32 (d, J=7.97 Hz, 2H) 5.16 (m, 1H)6.52 (m, 2H) 6.81 (m, 2H) 7.15 (m, 1H).

EXAMPLE 70

1-((4-(2-oxo-1,3-oxazolidin-3-yl))-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one(compound 1) and1-(4-(N-(2-(N′,N′-dimethylamino)ethyl))-N-(t-butoxycarbonyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one(compound 2)

By the same procedure as described in Reference Example 27→ReferenceExample 28 using the compound prepared in Example 63 and dimethylamine,the compounds (1) and (2) of the present invention having the followingphysical data respectively was obtained.

EXAMPLE 70(1)

TLC:Rf 0.22 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 1.71 (m, 1H) 1.98 (m, 1H) 2.37 (m, 1H) 2.51 (m, 1H) 2.68(m, 3 H) 3.34 (d, J=7.69 Hz, 2H) 3.99 (m, 2H) 4.49 (m, 2H) 6.82 (m, 2H)7.15 (m, 1H) 7.61 (m, 2H).

EXAMPLE 70(2)

TLC:Rf 0.51 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.48 (s, 9H) 1.70 (m, 1H) 1.99 (m, 1H) 2.26 (s, 6H) 2.36(m, 1H) 2.51 (m, 3H) 2.69 (m, 3H) 3.32 (d, J=7.97 Hz, 2H) 3.68 (t,J=7.42 Hz, 2H) 6.82 (m, 2H)7.14 (m, 1H)7.36 (m, 2H).

EXAMPLE 71

1-(4-(2-(N,N-dimethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 70(2), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.69 (m, 1H) 1.95 (m, 1H) 2.23 (s, 6H) 2.34 (m, 1H) 2.49(m, 3 H) 2.66 (m, 3H) 3.05 (q, J=5.04 Hz, 2H) 3.33 (d, J=7.69 Hz, 2H)4.61 (t, J=4.53 Hz, 1H)6.57 (s, 2H)6.81 (m, 2H)7.15 (m, 1H).

EXAMPLE 72

1-(4-(2-(morpholin-4-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 70 using morpholineinstead of dimethylamine, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.95 (m, 1H) 2.33 (m, 1H) 2.49 (m, 5H) 2.65(m, 5 H) 3.09 (q, J=4.85 Hz, 2H) 3.33 (d, J=7.69 Hz, 2H) 3.71 (m, 4H)4.60 (m, 1H) 6.59 (m, 2H)6.81 (m, 2H)7.15 (m, 1H).

EXAMPLES 72(1)˜72(5)

By the same procedure as described in Example 72 using the correspondingamine derivatives instead of morpholine, the following compounds of thepresent invention were obtained.

EXAMPLE 72(1)

1-(4-(2-(N,N-diethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.01 (t, J=7.14 Hz, 6H) 1.69 (m, 1H) 1.92 (m, 1H) 2.33 (m,1H) 2.51 (m, 5H) 2.65 (m, 5H) 3.02 (m, 2H) 3.32 (d, J=8.24 Hz, 2H) 4.67(m, 1H) 6.57 (m, 2H) 6.81 (m, 2H) 7.14 (m, 1H).

EXAMPLE 72(2)

1-(4-(2-(piperidin-1-yl)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.51 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.46 (m, 2H) 1.65 (m, 5H) 1.94 (m, 1H) 2.33 (m, 5H) 2.50(m, 3 H) 2.66 (m, 3H) 3.06 (m, 2H) 3.33 (d, J=7.97 Hz, 2H) 4.72 (m, 1H)6.58 (m, 2H) 6.81 (m, 2H) 7.15 (m, 1H).

EXAMPLE 72(3)

1-(4-(2-(imidazol-1-yl)ethylamino)-2,4-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one

TLC:Rf 0.45 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.69 (m, 1H) 1.95 (m, 1H) 2.33 (m, 1H) 2.50 (m, 1H) 2.66(m, 3 H) 3.33 (m, 4H) 4.11 (m, 2H) 4.67 (m, 1H) 6.42 (s, 2H) 6.82 (m,2H) 6.95 (s, 1H) 7.07 (s, 1H) 7.14 (m, 1H) 7.51 (s, 1H).

EXAMPLE 72(4)

1(4-(2-pyrrolidin-1-yl)ethylamino-2,6-dichlorophenyl-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.19 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.74 (m, 5H) 1.94 (m, 1H) 2.33 (m, 1H) 2.49 (m, 5H) 2.67(m, 5 H) 3.10 (m, 2H) 3.32 (d, J=7.69 Hz, 2H) 4.64 (t, J=4.67 Hz, 1H)6.57 (m, 2H) 6.81 (m, 2H)7.15 (m, 1H).

EXAMPLE 72(5)

1-(4-(2-(4-methylpiperazin-1-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.47 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.68 (m, 1H) 1.96 (m, 1H) 2.38 (m, 12H) 2.64 (m, 6H) 3.07(m, 2 H) 3.33 (d, J=7.69 Hz, 2H) 4.63 (m, 1H) 6.57 (m, 2H) 6.81 (m, 2H)7.15 (m, 1H).

EXAMPLE 73

1-(4-(N-(2-aminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 63 (677 mg) intetrahydrofuran (15 ml) were added triphenylphosphine (658 mg),phthalimide (206 mg) and diethylazodicarboxylate (40% solution intoluene, 1.02 ml). The reaction mixture was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated and the residue waspurified by column chromatography on silica gel (hexane:ethylacetate=1:1) to give the phthalamide derivative (776 mg). To a solutionof the obtained phthalamide derivative (241 mg) in methanol (5 ml) wasadded hydrazine 1H₂O (90 μl). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was filtrated and thefiltrate was concentrated. The residue was purified by preparative TLC(dichloromethane:methanol=9:1) to give the compound of the presentinvention (112 mg) having the following physical data.

TLC:Rf 0.22 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.47 (s, 9H) 1.71 (m, 1H) 1.98 (m, 1H) 2.35 (m, 1H) 2.51(m, 1 H) 2.69 (m, 3H) 2.90 (m, 2H) 3.32 (d, J=7.69 Hz, 2H) 3.66 (t,J=6.87 Hz, 2H) 6.82 (m, 2H) 7.16 (m, 1H) 7.33 (m, 2H).

EXAMPLE 74

1-(4-(2-methanesulfonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 41 Example 48 using thecompound prepared in Example 73, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.40 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.68 (m, 1H) 1.95 (m, 1H) 2.34 (m, 1H) 2.51 (m, 1H) 2.68(m, 3 H) 2.93 (s, 3H) 3.12 (m, 2H) 3.26 (m, 2H) 3.33 (d, J=7.69 Hz, 2H)4.85 (m, 1H) 5.41 (m, 1H) 6.41 (s, 2H) 6.82 (m, 2H) 7.15 (m, 1H).

EXAMPLE 75

1-(4-(N-(2-methylcarbonylaminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 73 (279 mg) intetrahydrofuran (5 ml) were added triethylamine (220 μl) and aceticanhydride (162 mg). The reaction mixture was stirred at room temperaturefor 30 minutes. Ethyl acetate was added to the reaction mixture, whichwas washed with 1N hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate:methanol=1:0→19:1) to givethe compound of the present invention (148 mg) having the followingphysical data.

TLC:Rf 0.49 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.47 (s, 9H) 1.71 (m, 1H) 1.98 (m, 4H) 2.36 (m, 1H) 2.51(m, 1 H) 2.68 (m, 3H) 3.33 (d, J=7.69 Hz, 2H) 3.45 (m, 2H) 3.76 (t,J=5.77 Hz, 2H) 5.92 (m, 1H) 6.83 (m, 2H) 7.15 (m, 1H) 7.30 (m, 2H).

EXAMPLE 76

1-(4-(2-methylcarbonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 48 using the compoundprepared in Example 75, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.29 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.95 (m, 4H) 2.33 (m, 1H) 2.49 (m, 1H) 2.66(m, 3 H) 3.04 (m, 2H) 3.36 (m, 4H) 4.88 (t, J=4.94 Hz, 1H) 6.42 (s, 2H)6.57 (m, 1H) 6.82 (m, 2H) 7.14 (m, 1H).

EXAMPLE 77

1-(4-(N-(2-aminocarbonylaminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 73 (203 mg) in aceticacid (1 ml) and water (1 ml) was added sodium cyanate (200 mg). Thereaction mixture was stirred at 80° C. for 1 hour. Ethyl acetate wasadded to the reaction mixture, which was washed with a saturated aqueoussodium hydrogen carbonate solution and brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was purified bypreparative TLC (ethyl acetate:methanol=19:1) to give the compound ofthe present invention (92 mg) having the following physical data.

TLC:Rf 0.42 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.48 (s, 9H) 1.71 (m, 1H) 2.00 (m, 1H) 2.36 (m, 1H) 2.50(m, 1 H) 2.67 (m, 3H) 3.37 (m, 4H) 3.75 (m, 2H) 4.53 (br. s., 2H) 4.90(m, 1H) 6.84 (m, 2H)7.14 (m, 1H)7.33 (m, 2H).

EXAMPLE 78

1-(4-(2-aminocarbonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 48 using the compoundprepared in Example 77, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.36 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.69 (m, 1H) 1.96 (m, 1H) 2.33 (m, 1H) 2.49 (m, 1H) 2.65(m, 3 H) 3.04 (m, 2H) 3.31 (m, 4H) 4.67 (s, 2H) 5.03 (m, 1H) 5.67 (m,1H) 6.45 (m, 2 H) 6.82 (m, 2H)7.15 (m, 1H).

EXAMPLE 79

1-(4-(2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 63 (200 mg) intetrahydrofuran (10 ml) were added triphenylphosphine (195 mg),4,4-dimethyl-2,5-dioxoimidazolidine (58 mg) and diethylazodicarboxylate(40% solution in toluene, 302 μl) and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated. Theobtained residue was purified by column chromatography on silica gel(hexane:ethyl acetate=3:7) to give the imidazolidine compound. To asolution of the imidazolidine compound in dichloromethane (2 ml) andwater (0.2 ml) was added trifluoroacetic acid (2 ml) at 0° C. Thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was concentrated and dissolved in ethyl acetate. Theethyl acetate solution was washed with a saturated aqueous sodiumhydrogen carbonate solution and brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by preparative TLC(hexane:ethyl acetate=1:4) to give the compound of the present invention(145 mg) having the following physical data.

TLC:Rf 0.33 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.39 (s, 6H) 1.68 (m, 1H) 1.94 (m, 1H) 2.33 (m, 1H) 2.48(m, 1 H) 2.65 (m, 3H) 3.31 (m, 4H) 3.77 (m, 2H) 4.49 (t, J=5.31 Hz, 1H)5.46 (s, 1H) 6.56 (m, 2H) 6.81 (m, 2H) 7.14 (m, 1H).

EXAMPLE 80

1-(3-amino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 16(11), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.55 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 7.25-7.06 (m, 2H), 6.87-6.76 (m, 2H), 6.61-6.46 (m, 2H),3.79-3.60 (m, 2H), 3.47-3.14 (m, 2H), 2.74-2.20 (m, 5H), 2.05-1.90 (m,1H), 1.79-1.60 (m, 1H).

EXAMPLE 81

1-(3-methylcarbonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 75 using the compoundprepared in Example 80, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.55 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 8.73-8.63 (m, 1H), 7.53-7.41 (m, 1H), 7.27-7.19 (m, 1H),7.17-7.08 (m, 1H), 7.02-6.90 (m, 1H), 6.88-6.64 (m, 2H), 3.50-3.25 (m,2H), 2.75-2.25 (m, 5H), 2.08-1.91 (m, 4H), 1.82-1.67 (m, 1H).

EXAMPLE 82

1-(3-methanesulfonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 41 using the compoundprepared in Example 80, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.41 (ethyl acetate);

NMR (CDCl₃):d 7.44-7.28 (m, 2H), 7.19-6.93 (m, 3H), 6.88-6.72 (m, 2H),3.52-3.18 (m, 2H), 3.07-2.90 (m, 3H), 2.78-2.48 (m, 4H), 2.41-2.26 (m,1H), 2.10-1.92 (m, 1H), 1.83-1.67 (m, 1H).

EXAMPLE 83

1-(3-ethoxycarbonylmethylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 51 using ethylbromoacetate and the compound prepared in Example 80 instead of methyliodide, the compound of the present invention having the followingphysical data was obtained.

TLC:Rf 0.24 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 7.26-7.08 (m, 2H), 6.88-6.74 (m, 2H), 6.53-6.39 (m, 2H),4.47-4.34 (m, 1H), 4.30-4.18 (m, 2H), 3.90-3.78 (m, 2H), 3.50-3.18 (m,2H), 2.74-2.20 (m, 5H), 2.08-1.90 (m, 1H), 1.80-1.62 (m, 1H), 1.37-1.22(m, 3H).

EXAMPLE 84

1-(3-carboxylmethylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 83, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.51 (ethyl acetate:methanol:water=6:3:1);

NMR (CDCl₃):d 7.45-7.32 (m, 1H), 7.25-7.12 (m, 2H), 7.08-6.98 (m, 1H),6.53-6.45 (m, 2H), 3.82-3.72 (m, 2H), 3.25-3.15 (m, 2H), 2.74-2.66 (m,2H), 2.41-2.13 (m, 3H), 1.90-1.78 (m, 1H), 1.70-1.47 (m, 1H).

EXAMPLE 85

1-(3-(2-hydroxyethylamino)-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 37 using the compoundprepared in Example 84, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.46 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 7.14-7.05 (m, 2H), 6.84-6.67 (m, 2H), 6.28-6.10 (m, 2H),3.92-3.75 (m, 2H), 3.27-3.123 (m, 3H), 2.61-2.47 (m, 4H), 2.39-2.25 (m,2H), 1.85-1.62 (m, 2H).

EXAMPLE 86

1-(4-(2-(N,N-dimethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one

By the same procedure as described in Example 13→Example 48 using thecompound prepared in Example 16(12) and2-(N,N-dimethylamino)-1-chloroethane, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.39 (chloroform:methanol=4:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.96 (m, 1H) 2.23 (m, 6H) 2.39 (m, 2H) 2.52(t, J=5.70 Hz, 2H) 2.66 (m, 1H) 2.74 (d, J=7.10 Hz, 2H) 3.05 (q, J=4.80Hz, 2H) 3.35 (d, J=8.00 Hz, 2H) 4.62 (m, 1H) 6.57 (m, 2H) 7.05 (m, 2H)7.19 (m, 2H).

EXAMPLE 87

1-(2,6-dichlorophenyl)-5-(4-aminobenzyl)piperidin-2-one

By the same procedure as described in Example 10 using the compoundprepared in Example 16(4), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.31 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 7.41-7.33 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.97 and 6.63(each d, J=8.4 Hz, each 2H), 3.66-3.52 (m, 2H), 3.37-3.25 (m, 2H),2.73-2.42 (m, 4H), 2.39-2.20 (m, 1H), 2.07-1.93 (m, 1H), 1.75-1.60 (m,1H).

EXAMPLE 88

1-(2,6-dichlorophenyl)-5-(4-cyclohexylcarbonylaminobenzyl)piperidin-2-one

By the same procedure as described in Example 12 using the compoundprepared in Example 87 and cyclohexanecarbonyl chloride, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.54 (chloroform:methanol=9:1);

NMR (DMSO-d₆):d 9.72 (s, 1H), 7.58-7.50 (m, 2H), 7.50 (d, J=8.1 Hz, 2H),7.37 (t, J=7.8 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 3.26-3.16 (m, 2H),2.66-2.59 (m, 2H), 2.50-2.39 (m, 2H), 2.38-2.20 (m, 2H), 1.98-1.51 (m,7H), 1.48-1.11 (m, 5H).

EXAMPLE 89

1-(2,6-dichlorophenyl)-5-(4-methylcarbonylaminobenzyl)piperidin-2-one

By the same procedure as described in Example 75 using the compoundprepared in Example 87, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.42 (chloroform:methanol=9:1);

NMR (DMSO-d₆):d 9.85 (s, 1H), 7.58-7.52 (m, 2H), 7.47 (d, J=8.4 Hz, 2H),7.37 (t, J=8.1 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 3.25-3.16 (m, 2H),2.66-2.60 (m, 2H), 2.50-2.39 (m, 2H), 2.33-2.19 (m, 1H), 2.00 (s, 3H),1.94-1.82 (m, 1H), 1.67-1.51 (m, 1H).

EXAMPLE 90

1-(4-amino-2-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 16(9), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.22 (ethyl acetate);

NMR (CDCl₃):d 1.70 (m, 1H) 1.94 (m, 1H) 2.26 (m, 1H) 2.56 (m, 4H) 3.30(m, 2 H) 3.76 (m, 2H) 6.54 (m, 1H) 6.77 (m, 3H) 6.95 (dd, J=13.32, 8.38Hz, 1H) 7.12 (m, 1H).

EXAMPLE 91

1-(2,6-dichlorophenyl)-5-(2-hydroxymethylbenzyl)piperidin-2-one

To a solution of the compound prepared in Example 16(8) (3.86 g) inmethanol (20 ml) was added concentrated hydrochloric acid (0.5 ml). Thereaction mixture was stirred at 65° C. for 3.5 hours. The reactionmixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and then the reaction mixture was concentrated andextracted with ethyl acetate. The extract was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was washed with isopropyl ether to give the compound ofthe present invention (2.74 g) having the followed physical data.

TLC:Rf 0.26 (hexane:ethyl acetate=2:3);

NMR (CDCl₃):d 1.77 (m, 1H), 2.01 (m, 1H), 2.57-2.35 (m, 2H), 2.66 (m,1H), 2.87-2.67 (m, 2H), 3.45-3.32 (m, 2H), 4.75 (d, J=10.2 Hz, 2H),7.33-7.17 (m, 4H), 7.43-7.35 (m, 3H).

EXAMPLE 92

1-(2,6-dichlorophenyl)-5-(2-aminomethylbenzyl)piperidin-2-onehydrochloride

By the same procedure as described in Example 73→Reference Example 31using the compound prepared in Example 91, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.18 (chloroform:methanol=9:1);

NMR (CD₃OD):d 1.80 (m, 1H) 2.01 (m, 1H) 2.37 (m, 1H) 2.52 (m, 1H) 2.63(m, 1 H) 2.86 (m, 2H) 3.38 (m, 1H) 3.49 (m, 1H) 4.22 (s, 2H) 7.35 (m,4H) 7.42 (m, 1 H) 7.49 (m, 2H).

EXAMPLE 93

1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonylaminomethylbenzyl)piperidin-2-one

To a solution of the compound prepared in Example 92 (130 mg) intetrahydrofuran (5 ml) was addedN-(3-t-butyl-1-methylpyrazol-5-yl)-1-(4-dimethylidenehydropyridyl)carboamide(108 mg) at room temperature. The reaction mixture was stirred at roomtemperature for 15 minutes. 1N hydrochloric acid was added to thereaction mixture, which was extracted with ethyl acetate. The extractwas washed 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate andconcentrated. The obtained residue was purified by preparative TLC(chloroform:methanol=9:1, twice) to give the compound of the presentinvention having the following physical data.

TLC:Rf 0.50 (chloroform:methanol 9:1);

NMR (CDCl₃):d 1.25 (s, 9H) 1.73 (m, 1H) 1.95 (m, 1H) 2.56 (m, 5H) 3.38(d, J=7.69 Hz, 2H) 3.62 (s, 3H) 4.45 (d, J=5.49 Hz, 2H) 5.11 (m, 1H)5.97 (s, 1H) 6.37 (s, 1H) 7.26 (m, 7H).

EXAMPLE 94

1-(2,6-dichlorophenyl)-5-(2-benzylaminocarbonylaminomethylbenzyl)piperidin-2-one

By the same procedure as described in Reference Example 13 using thecompound prepared in Example 92 and benzylisocyanate, the compound ofthe present invention having the following physical data was obtained.

TLC:Rf 0.34 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.65 (m, 1H), 1.89 (m, 1H), 2.38 (m, 3H), 2.71 (m, 2H),3.29 (m, 2H), 4.21 (d, J=5.49 Hz, 2H), 4.28 (d, J=4.94 Hz, 2H), 6.38 (m,2H), 7.24 (m, 10H), 7.57 (m, 2H).

EXAMPLES 94(1)˜94(6)

By the same procedure as described in Example 94 using the correspondingisocyanate instead of benzylisocyanate, the following compounds of thepresent invention were obtained.

EXAMPLE 94(1)

1-(2,6-dichlorophenyl)-5-(2-phenylaminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.33 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.64 (m, 1H), 1.92 (m, 1H), 2.39 (m, 3H), 2.76 (d,J=6.87 Hz, 2 H), 3.28 (m, 2H), 4.33 (d, J=5.49 Hz, 2H), 6.49 (t, J=5.49Hz, 1H), 6.88 (t, J=7.28 Hz, 1H), 7.27 (m, 9H), 7.54 (m, 2H), 8.46 (s,1H).

EXAMPLE 94(2)

1-(2,6-dichlorophenyl)-5-(2-cyclohexylaminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.32 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.15 (m, 6H), 1.67 (m, 7H), 2.37 (m, 3H), 2.73 (m, 2H),3.30 (m, 2H), 4.22 (m, 2H), 5.76 (d, J=7.69 Hz, 1H), 6.05 (t, J=5.49 Hz,1H), 7.15 (m, 4 H), 7.37 (t, J=7.97 Hz, 1H), 7.55 (m, 2H).

EXAMPLE 94(3)

1-(2,6-dichlorophenyl)-5-(2-(3-trifluoromethylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.32 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.67 (m, 1H), 1.89 (m, 1H), 2.38 (m, 3H), 2.76 (m, 2H),3.27 (m, 2H), 4.36 (d, J=5.22 Hz, 2H), 6.67 (t, J=5.22 Hz, 1H), 7.37 (m,10H), 7.96 (s, 1 H), 8.88 (s, 1H).

EXAMPLE 94(4)

1-(2,6-dichlorophenyl)-5-(2-ethylaminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.29 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 0.97 (t, J=7.00 Hz, 3H), 1.65 (m, 1H), 1.88 (m, 1H),2.35 (m, 3 H), 2.73 (m, 2H), 3.00 (m, 2H), 3.28 (m, 2H), 4.23 (d, J=5.49Hz, 2H), 5.81 (t, J=4.67 Hz, 1H), 6.16 (t, J=5.49 Hz, 1H), 7.18 (m, 4H),7.38 (t, J=7.97 Hz, 1H), 7.58 (m, 2H).

EXAMPLE 94(5)

1-(2,6-dichlorophenyl)-5-(2-(3-methylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.49 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.66 (m, 1H), 1.89 (m, 1H), 2.22 (s, 3H), 2.37 (m, 3H),2.76 (d, J=6.87 Hz, 2H), 3.25 (m, 2H), 4.33 (d, J=5.08 Hz, 2H), 6.47 (t,J=5.08 Hz, 1H), 6.70 (d, J=7.14 Hz, 1H), 7.20 (m, 8H), 7.53 (m, 2H),8.37 (s, 1H).

EXAMPLE 94(6)

1-(2,6-dichlorophenyl)-5-(2-(2-trifluoromethylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one

TLC:Rf 0.51 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.67 (m, 1H), 1.88 (m, 1H), 2.35 (m, 3H), 2.77 (m, 2H),3.29 (m, 2H), 4.35 (d, J=5.22 Hz, 2H), 7.25 (m, 7H), 7.57 (m, 4H), 7.80(s, 1H), 7.97 (d, J=8.24 Hz, 1H).

EXAMPLE 95

1-(2,6-dichlorophenyl)-5-(2-methylcarbonylaminomethylbenzyl)piperidin-2-one

By the same procedure as described in Example 75 using the compoundprepared in Example 92, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.61 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.75 (m, 1H) 1.99 (s, 3H) 2.00 (m, 1H) 2.33 (m, 1H) 2.48(m, 1 H) 2.69 (m, 3H) 3.38 (m, 2H) 4.47 (d, J=5.49 Hz, 2H) 5.67 (s, 1H)7.23 (m, 5H) 7.37 (m, 2H).

EXAMPLE 96

1-(2,6-dichlorophenyl)-5-(2-(3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalene-2-yl)aminocarbonylaminomethylbenzyl)piperidin-2-one

To a solution of 1,1′-carbonylimidazole (45 mg) in tetrahydrofuran (3ml) was added a solution of the compound prepared in Example 92 (100 mg)in tetrahydrofuran (1 ml) at 0° C. The mixture was stirred at roomtemperature for 30 minutes. To the reaction mixture was added a solutionof 3,8,8-trimethyl-2-5,6,7,8-tetrahydronaphthylamine (55 mg) intetrahydrofuran (1 ml). The reaction mixture was stirred at roomtemperature overnight. To the reaction mixture were added ethyl acetateand 1N hydrochloric acid sequentially and the reaction mixture wasextracted. The water layer was alkalinized with a saturated aqueoussodium hydrogen carbonate. The water layer was extracted with ethylacetate. The extract was washed with brine, dried over anhydrous sodiumsulfate and concentrated. The obtained residue was purified bypreparative TLC (chloroform:methanol=9:1) to give the compound of thepresent invention (12 mg) having the following physical data.

TLC:Rf 0.34 (chloroform:methanol 40:1);

NMR (CDCl₃):d 1.18 (s, 6H), 1.67 (m, 5H), 1.95 (m, 1H), 2.17 (s, 3H),2.37 (m, 2 H), 2.72 (m, 5H), 3.38 (d, J=7.69 Hz, 2H), 4.48 (d, J=5.22Hz, 2H), 4.71 (t, J=5.22 Hz, 1H), 5.91 (s, 1H), 6.89 (s, 1H), 7.20 (m,6H), 7.37 (m, 2H).

EXAMPLE 97

1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonyloxymethylbenzyl)piperidin-2-one

By the same procedure as described in Example 93 using the compoundprepared in Example 91, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.34 (chloroform:methanol 19:1);

NMR (DMSO-d₆):d 1.17 (s, 9H), 1.66 (m, 1H), 1.85 (m, 1H), 2.36 (m, 3H),2.78 (m, 2H), 3.29 (m, 2H), 3.53 (s, 3H), 5.20 (s, 2H), 5.93 (s, 1H),7.26 (m, 3H), 7.39 (m, 2H), 7.54 (m, 2H), 9.57 (s, 1H).

EXAMPLE 98

1-(2,6-dichlorophenyl)-5-(2-formylbenzyl)piperidin-2-one

To a solution of the compound prepared in Example 91 (170 mg) in ethylacetate (3 ml) and dimethylsulfoxyde (3 ml) were added triethylamine(387 μl) and sulfur trioxide pyridine complex (223 mg) at 0° C. Thereaction mixture was stirred at room temperature for 30 minutes. To thereaction mixture was added ethyl acetate. The reaction mixture waswashed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate andconcentrated to give the compound of the present invention (169 mg)having the following physical data.

TLC:Rf 0.49 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 1.79 (m, 1H) 1.99 (m, 1H) 2.35 (m, 1H) 2.48 (m, 1H) 2.67(m, 1 H) 3.07 (dd, J=12.91, 7.42 Hz, 1H) 3.21 (dd, J=12.91, 6.04 Hz, 1H)3.42 (d, J=7.97 Hz, 2H) 7.20 (t, J=7.97 Hz, 1H) 7.29 (m, 1H) 7.38 (m,2H) 7.50 (m, 2H) 7.84 (m, 1H) 10.19 (s, 1H).

EXAMPLE 99

1-(2,6-dichlorophenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one

To a solution of the compound prepared in Example 98 (165 mg) inacetonitrile (10 ml) were added diisopropylethylamine (120 μl), lithiumchloride (26 mg) and dimethylmethoxycarbonylmethyl phosphonate (125 mg).The reaction mixture was stirred at room temperature for 24 hours. Tothe reaction mixture was added ethyl acetate. The reaction mixture waswashed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate andconcentrated to give the compound of the present invention (190 mg)having the following physical data.

TLC:Rf 0.49 (hexane:ethyl acetate=3:2);

NMR (CDCl₃):d 1.72 (m, 1H) 1.99 (m, 1H) 2.30 (m, 1H) 2.49 (m, 1H) 2.68(m, 1 H) 2.85 (m, 2H) 3.38 (m, 2H) 3.83 (s, 3H) 6.39 (d, J=15.66 Hz, 1H)7.30 (m, 6H) 7.59 (m, 1H) 8.00 (d, J=15.66 Hz, 1H).

EXAMPLE 100

1-(2,6-dichlorophenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 99, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.43 (ethyl acetate);

NMR (CDCl₃):d 1.76 (m, 1. H) 1.99 (m, 1H) 2.32 (m, 1H) 2.51 (m, 1H) 2.69(m, 1 H) 2.87 (m, 2H) 3.36 (m, 2H) 6.41 (d, J=15.66 Hz, 1H) 7.29 (m, 6H)7.64 (dd, J=7.42, 1.37 Hz, 1H) 8.09 (d, J=15.66 Hz, 1H).

EXAMPLE 101

1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonyl)ethylpiperidin-2-one

By the same procedure as described in Reference Example 37→ReferenceExample 15 using the compound prepared in Example 100 and5-amino-1-methyl-3-t-butylpyrazole, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.52 (ethyl acetate);

NMR (CDCl₃):d 1.26 (s, 9H) 1.74 (m, 1H) 2.00 (m, 1H) 2.39 (m, 2H) 2.68(m, 5 H) 3.07 (t, J=7.55 Hz, 2H) 3.38 (m, 2H) 3.51 (s, 3H) 6.04 (s, 1H)7.17 (m, 6H) 7.35 (m, 2H).

EXAMPLE 102

1-(2,6-dimethylphenyl)-5-(2-hydroxybenzyl)piperidin-2-one

By the same procedure as described in Example 48 using the compoundprepared in Example 16(3), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.37 (hexane:ethyl acetate=1:4);

NMR (CDCl₃):d 1.62 (m, 1H).1.98 (m, 1H), 2.09 (s, 3H), 2.21 (s, 3H),2.55-2.35 (m, 2H), 2.73-2.62 (m, 3H), 3.30-3.19 (m, 2H), 6.12 (s, 1H),6.65 (m, 1H), 6.80 (m, 1H), 7.14-6.99 (m, 5H).

EXAMPLE 103

1-(2,6-dimethylphenyl)-5-(2-isobutyloxybenzyl)piperidin-2-one

By the same procedure as described in Example 51 using the compoundprepared in Example 102 and 1-iodo-2-methylpropane, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.56 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 7.18 (m, 1H), 7.16-7.04 (m, 4H), 6.88-6.81 (m, 2H),3.79-3.68 (m, 2H), 3.30-3.20 (m, 2H), 2.76 (dd, J=12.9, 6.3 Hz, 1H),2.71-2.58 (m, 2H), 2.48 (ddd, J=18.3, 12.0, 6.6 Hz, 1H), 2.41 (m, 1H),2.22 (s, 3H), 2.15-1.94 (m, 5H), 1.63 (m, 1H), 1.04 (d, J=6.9 Hz, 6H).

EXAMPLE 104

1-(2,6-dimethylphenyl)-5-(2-ethoxycarbonylmethoxybenzyl)piperidin-2-one

By the same procedure as described in Example 103 using ethylbromoacetate instead of 1-iodo-2-methylpropane, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.35 (hexane:ethyl acetate=2:3);

NMR (CDCl₃):d 1.27 (t, J=7.14 Hz, 3H) 1.71 (m, 1H) 2.01 (m, 1H) 2.12 (s,3H) 2.22 (s, 3H) 2.49 (m, 2H) 2.66 (m, 1H) 2.77 (d, J=7.14 Hz, 2H) 3.26(m, 2H) 4.24 (q, J=7.14 Hz, 2H) 4.63 (s, 2H) 6.73 (m, 1H) 6.93 (m, 1H)7.12 (m, 5H).

EXAMPLE 105

1-(2,6-dimethylphenyl)-5-(2-carboxymethoxybenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 104, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.24 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.67 (m, 1H) 2.01 (m, 1H) 2.11 (s, 3H) 2.22 (s, 3H) 2.56(m, 2H) 2.74 (m, 3H) 3.26 (m, 2H) 4.65 (m, 2H) 6.74 (m, 1H) 6.91 (m, 1H)7.12 (m, 5H).

EXAMPLE 106

1-(2,6-dimethylphenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonylmethyloxyphenylmethyl)piperidin-2-one

By the same procedure as described in Example 37 using the compoundprepared in Example 105 and 5-amino-1-methyl-3-t-butylpyrazole, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.28 (ethyl acetate);

NMR (CDCl₃):d 1.29 (s, 9H) 1.70 (m, 1H) 2.04 (m, 4H) 2.20 (s, 3H) 2.45(m, 2H) 2.68 (m, 1H) 2.78 (d, J=7.42 Hz, 2H) 3.27 (m, 2H) 3.61 (s, 3H)4.69 (s, 2H) 6.14 (s, 1H) 6.88 (d, J=8.24 Hz, 1H) 7.07 (m, 4H) 7.23 (m,2H) 7.92 (s, 1H).

EXAMPLE 107

1-(4-methoxycarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 16(1) (0.93 g) indimethylformamide (4.6 ml) were added methanol (4.6 ml), triethylamine(0.96 ml), 1,1′-bis(diphenylphosphono)ferrocene (126 mg) and palladiumacetate (51 mg). Under an atmosphere of carbon monoxide, the reactionmixture was stirred 70° C. for 2.5 hours. The reaction mixture wasdiluted with ethyl acetate and filtrated through Celite (proprietaryname). Water was added to the filtrate, which was extracted with t-butylmethyl ether. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1→0:1) togive the compound of the present invention (670 mg) having the followingphysical data.

TLC:Rf 0.23 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 7.80-7.73 (m, 2H), 7.17-7.07 (m, 1H), 6.87-6.73 (m, 2H),3.89 (s, 3H), 3.27-3.12 (m, 2H), 2.74-2.62 (m, 3H), 2.60-2.45 (m, 1H),2.40-2.22 (m, 4H), 2.16 (s, 3H), 2.07-1.95 (m, 1H), 1.78-1.61 (m, 1H).

EXAMPLE 108

1-(4-carboxyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 107, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.40 (ethyl acetate:methanol=5:1);

NMR (DMSO-d₆):d 13.00-12.70 (m, 1H), 7.66 (s, 2H), 7.43-7.33 (m, 1H),7.23-7.13 (m, 1H), 7.07-6.95 (m, 1H), 3.30-3.05 (m, 2H), 2.76-2.65 (m,2H), 2.47-2.35 (m, 2H), 2.30-2.20 (m, 1H), 2.16 and 2.07 (each s, each3H), 1.90-1.79 (m, 1H), 1.74-1.55 (m, 1H).

EXAMPLE 109

1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 108 (60 mg) in toluene(1 ml) were added oxalyl chloride (15 μl) and dimethylformamide (2drops). The reaction mixture was stirred at room temperature for 1.5hours. The obtained solution was added to a solution of2-(N,N-dimethylamine)ethylamine (21 μL), dimethylformamide (1 ml) andtriethylamine (68 μl) at room temperature. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was pouredin water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was washed t-butyl methyl ether/hexane to give thecompound of the present invention (21 mg) having the following physicaldata.

TLC:Rf 0.49 (ethyl acetate:methanol:triethylamine=10:9:1);

NMR (CDCl₃):d 7.48 (s, 2H), 7.18-7.07 (m, 1H), 6.88-6.67 (m, 3H), 3.49(brq, J=5.7 Hz, 2H), 3.29-3.12 (m, 2H), 2.77-2.62 (m, 3H), 2.60-2.45 (m,4H), 2.26 (s, 9H), 2.16 (s, 3H), 2.08-1.96 (m, 1H), 1.75-1.67 (m, 1H).

EXAMPLES 109(1)˜109(7)

By the same procedure as described in Example 109 using thecorresponding amine derivatives instead of2-(N,N-dimethylamine)ethylamine, the following compound of the presentinvention were obtained.

EXAMPLE 109(1)

1-(4-(3-(N,N-dimethylamino)propylaminocarbonyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.32 (ethyl acetate:methanol:triethylamine=10:9:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.81 (m, 2H) 2.00 (m, 1H) 2.15 (s, 3H) 2.25(s, 3H) 2.35 (m, 7H)2.53 (m, 3H)2.69 (m, 3H)3.20 (m, 2H)3.53 (m, 2H)6.80(m, 2H) 7.11 (m, 1H) 7.51 (m, 2H)8.29 (m, 1H).

EXAMPLE 109(2)

1-(4-methylaminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.61 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.70 (m, 1H) 2.01 (m, 1H) 2.14 (s, 3H) 2.23 (s, 3H) 2.31(m, 1H) 2.52 (m, 1H) 2.68 (m, 3H) 2.97 (m, 3H) 3.20 (m, 2H) 6.13 (m, 1H)6.82 (m, 2H) 7.12 (m, 1H)7.44 (s, 2H).

EXAMPLE 109(3)

1-(4-(N,N-dimethylamino)carbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.25 (ethyl acetate: triethylamine=9:1);

NMR (CDCl₃):d 1.69 (m, 1H) 2.01 (m, 1H) 2.11 (s, 3H) 2.21 (s, 3H) 2.29(m, 1H) 2.52 (m, 1H) 2.69 (m, 3H) 3.07 (m, 8H) 6.82 (m, 2H) 7.11 (m,3H).

EXAMPLE 109(4)

1-(4-(morpholin-4-yl)carbonyl-2,6-dimethylphenyl-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.28 (ethyl acetate: triethylamine=9:1);

NMR (CDCl₃):d 1.69 (m, 1H) 2.01 (m, 1H) 2.12 (s, 3H) 2.22 (s, 3H) 2.31(m, 1H) 2.52 (m, 1H) 2.69 (m, 3H) 3.16 (m, 2H) 3.63 (m, 8H) 6.81 (m, 2H)7.11 (m, 3H).

EXAMPLE 109(5)

1-(4-(4-methylpiperazin-1-yl)carbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-onehydrochloride

TLC:Rf 0.51 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (DMSO-d₆):d 1.64 (m, 1H) 1.84 (m, 1H) 2.06 (s, 3H) 2.15 (s, 3H) 2.28(m, 1 H) 2.41 (m, 4H) 2.73 (m, 7H) 3.06 (m, 4H) 3.25 (m, 2H) 7.03 (m,1H) 7.19 (m, 3 H) 7.40 (m, 1H) 10.97 (m, 1H).

EXAMPLE 109(6)

1-(4-(3-ethoxycarbonylpropyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.47 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 7.48 (brs, 2H), 7.19-7.06 (m, 1H), 6.88-6.73 (m, 2H),6.50-6.40 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.48 (brq, J=6.6 Hz, 2H),3.28-3.11 (m, 2H), 2.74-2.62 (m, 3H), 2.59-2.46 (m, 1H), 2.42 (t, J=7.2Hz, 2H), 2.36-2.21 (m, 4H), 2.15 (s, 3H), 2.06-1.87 (m, 3H), 1.75-1.65(m, 1H), 1.25 (t, J=7.2 Hz, 3H).

EXAMPLE 109(7)

1-(4-(2-ethoxycarbonylethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.52 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 7.47 (brs, 2H), 7.18-7.07 (m, 1H), 6.90-6.68 (m, 3H), 4.17(q, J=7.2 Hz, 2H), 3.70 (brq, J=6.0 Hz, 2H), 3.29-3.10 (m, 2H),2.75-2.45 (m, 6H), 2.39-2.22 (m, 4H), 2.15 (s, 3H), 2.07-1.94 (m, 1H),1.76-1.65 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).

EXAMPLES 110(1) AND 110(2)

By the same procedure as described in Example 36 using the compoundsprepared in Example 109(6) or Example 109(7), the following compound ofthe present invention were obtained.

EXAMPLE 110(1)

1-(4-(3-carboxypropyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.37 (ethyl acetate:methanol:water=7:2:1);

NMR (CDCl₃):d 7.49 (s, 2H), 7.19-7.08 (m, 1H), 7.07-6.93 (m, 1H),6.89-6.65 (m, 2H), 3.47-3.32 (m, 2H), 3.28-3.12 (m, 2H), 2.75-2.63 (m,3H), 2.60-2.45 (m, 1H), 2.40-2.26 (m, 3H), 2.21 and 2.17 (each s, each3H), 2.08-1.94 (m, 1H), 1.92-1.79 (m, 2H), 1.75-1.59 (m, 1H).

EXAMPLE 110(2)

1-(4-(2-carboxyethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.29 (ethyl acetate:methanol:water=7:2:1);

NMR (CDCl₃):d 7.45 (s, 2H), 7.18-7.07 (m, 1H), 6.90-6.73 (m, 3H),3.68-3.55 (m, 2H), 3.27-3.12 (m, 2H), 2.76-2.65 (m, 3H), 2.62-2.46 (m,3H), 2.40-2.26 (m, 1H), 2.23 and 2.14 (each s, each 3H), 2.07-1.93 (m,1H), 1.75-1.63 (m, 1H).

EXAMPLE 111

1-(4-(t-butoxycarbonyl)amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution the compound prepared in Example 108 (500 mg) in toluene(5 ml) were added butanol (5 ml), triethylamine (0.23 ml) anddiphenylphosphorylazide (0.35 ml). The reaction mixture was stirred at90° C. for 3 hours. To the reaction mixture was added ethyl bromoacetate(0.14 ml). The reaction mixture was stirred at room temperature. Thereaction mixture was concentrated. The obtained residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=3:1→1:3) togive the compound of the present invention (486 mg) having the followingphysical data.

TLC:Rf 0.27 (ethyl acetate:hexane=3:1);

NMR (CDCl₃):d 7.16-7.05 (m, 3H), 6.87-6.73 (m, 2H), 6.55 (s, 1H),3.26-3.10 (m, 2H), 2.74-2.60 (m, 3H), 2.53-2.45 (m, 1H), 2.33-2.21 (m,1H), 2.16 (s, 3H), 2.06 (s, 3H), 2.05-1.92 (m, 1H), 1.73-1.60 (m, 1H),1.50 (s, 9H).

EXAMPLE 112

1-(4-amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 31 using thecompounds prepared in Example 111, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.42 (ethyl acetate:methanol=5:1);

NMR (CDCl₃):d 1.64 (m, 1H) 1.94 (m, 1H) 2.01 (s, 3H) 2.11 (s, 3H) 2.28(m, 1H) 2.49 (m, 1H) 2.67 (m, 3H) 3.19 (m, 2H) 3.55 (m, 2H) 6.40 (s, 2H)6.83 (m, 2H) 7.12 (m, 1H).

EXAMPLE 112(1)

1-(4-aminomethyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 3→Example 73using the compounds prepared in Example 107, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.34 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.87 (m, 2H) 2.00 (m, 1H) 2.11 (s, 3H) 2.20(s, 3H) 2.32 (m, 1H) 2.51 (m, 1H) 2.68 (m, 3H) 3.21 (m, 2H) 3.79 (s, 2H)6.81 (m, 2H) 7.05 (m, 2H) 7.13 (m, 1H).

EXAMPLE 113

1-(4-(4-(tetrahydropyran-2-yloxy)but-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 16(1) (5 g) indimethylformamide (36 ml) were added 3-butynyloxytetrahydro-2-pyran(2.83 g) and triethylamine (12 ml) under an atmosphere of argon. To themixture was added bis(triphenylphosphine)palladium(II) chloride (0.86g). The reaction mixture was stirred at 90° C. for 1 hour. The reactionmixture was poured in ice water and extracted with t-butyl methyl ether.The extract was washed with water and brine, dried over anhydrous sodiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:2→3:1) to give thecompound of the present invention (5.09 g) having the following physicaldata.

TLC:Rf 0.24 (ethyl acetate);

NMR (CDCl₃):d 7.16-7.07 (m, 3H), 6.87-6.76 (m, 2H), 4.70-4.57 (m, 1H),3.96-3.80 (m, 2H), 3.67-3.40 (m, 2H), 3.30-3.13 (m, 2H), 2.75-2.60 (m,5H), 2.58-2.40 (m, 1H), 2.36-2.23 (m, 1H), 2.18 and 2.16 (each s,totally 3H), 2.08 and 2.07 (each s, totally 3H), 2.02-1.94 (m, 1H),1.89-1.77 (m, 2H), 1.74-1.46 (m, 5H).

EXAMPLE 114

1-(4-(4-hydroxybut-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 113 (5.09 g) inmethanol (50 ml) was added 2N hydrochloric acid (11 ml). The reactionmixture was stirred at room temperature for 10 minutes. The reactionmixture was poured in water and extracted with t-butyl methyl ether. Theextract was washed with water and brine, dried over anhydrous sodiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:3 methanol:ethylacetate=1:3) to give the compound of the present invention (0.94 g)having the following physical data.

TLC:Rf 0.29 (ethyl acetate);

NMR (CDCl₃):d 1.69 (m, 1H) 1.87 (m, 1H) 1.98 (m, 1H) 2.08 (s, 3H) 2.17(s, 3H) 2.29 (m, 1H) 2.50 (m, 1H) 2.66 (m, 5H) 3.20 (m, 2H) 3.77 (m, 2H)6.81 (m, 2H) 7.12 (m, 3H).

EXAMPLE 115

1-(4-(4-(N,N-dimethylamino)but-1-ynyl))-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 70 using the compoundsprepared in Example 114 and dimethylamine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.53 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.65 (m, 1H) 1.97 (m, 1H) 2.07 (s, 3H) 2.16 (s, 3H) 2.29(m, 7H) 2.51 (m, 5H)2.66 (m, 3H)3.18 (m, 2H)6.81 (m, 2H)7.11 (m, 3H).

EXAMPLES 115(1) AND 115(2)

By the same procedure as described in Example 115 using thecorresponding amine derivatives instead of dimethylamine, the followingcompounds of the present invention were obtained.

EXAMPLE 115(1)

1-(4-(4-morpholinobut-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.62 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.67 (m, 1H) 1.98 (m, 1H) 2.07 (s, 3H) 2.16 (s, 3H) 2.29(m, 1H) 2.57 (m, 12H) 3.19 (m, 2H) 3.72 (m, 4H) 6.82 (m, 2H) 7.11 (m,3H).

EXAMPLE 115(2)

1-(4-(4-(4-methylpiperazin-1-yl)but-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

TLC:Rf 0.40 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.66 (m, 1H) 1.98 (m, 1H) 2.06 (s, 3H) 2.16 (s, 3H) 2.30(m, 4H) 2.55 (m, 16H) 3.19 (m, 2H) 6.81 (m, 2H) 7.13 (m, 3H).

EXAMPLE 116

1-(4-(4-(N,N-dimethylamino)butyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompounds prepared in Example 115, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.44 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.58 (m, 5H) 1.98 (m, 1H) 2.07 (s, 3H) 2.17 (s, 3H) 2.21(s, 6H). 2.30 (m, 3H) 2.50 (m, 3H) 2.69 (m, 3H) 3.20 (m, 2H) 6.80 (m,2H) 6.89 (s, 2H) 7.13 (m, 1H).

EXAMPLE 117

(E)-1-(4-(2-(2-(N,N-dimethylamino)ethyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 115 (74 mg) intetrahydrofuran (3.4 ml) were added quinoline (11 mg) andpalladium-barium sulfate (22 mg) under an atmosphere of argon. Under anatmosphere of hydrogen, the reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was filtrated throughCelite (proprietary name) and concentrated. The obtained residue waspurified by column chromatography on silica gel (ethylacetate:methanol:triethylamine=1:0:0→20:1:1) to give the compound of thepresent invention (57 mg) having the following physical data.

TLC:Rf 0.51 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.69 (m, 1H) 2.00 (m, 1H) 2.10 (s, 3H) 2.20 (s, 3H) 2.24(s, 6H) 2.29 (m, 1H) 2.39 (m, 2H) 2.52 (m, 3H) 2.67 (m, 3H) 3.21 (m, 2H)5.63 (m, 1H) 6.36 (m, 1H) 6.82 (m, 2H) 7.01 (s, 2H) 7.13 (m, 1H).

EXAMPLE 118

1-(4-(5-hydroxypent-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 16(1) (408 mg) indimethylformamide (2.5 ml) were added triethylamine (2.5 ml) and4-pentyn-1-ol (168 mg). Under an atmosphere of argon, to the mixturewere added tetrakis(triphenylphosphine)palladium(0) (46 mg) and copperiodide (23 mg). The reaction mixture was stirred at 80° C. for 2 hours.The reaction mixture was diluted with ethyl acetate, washed 1Nhydrochloric acid, a saturated anhydrous sodium hydrogen carbonatesolution and brine, dried over anhydrous sodium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=3:7→1:9) to give the compound of thepresent invention (276 mg) having the following physical data.

TLC:Rf 0.28 (hexane:ethyl acetate=1:4);

NMR (CDCl₃):d 1.51 (m, 1H) 1.68 (m, 1H) 1.83 (m, 2H) 2.00 (m, 1H) 2.07(s, 3 H) 2.16 (s, 3H) 2.29 (m, 1H) 2.50 (m, 3H) 2.66 (m, 3H) 3.18 (m,2H) 3.80 (m, 2 H) 6.81 (m, 2H) 7.14 (m, 3H).

EXAMPLE 119

1-(4-(5-hydroxypentyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompounds prepared in Example 118, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.28 (ethyl acetate);

NMR (CDCl₃):d 1.41 (m, 2H) 1.65 (m, 6H) 1.99 (m, 1H) 2.08 (s, 3H) 2.17(s, 3H) 2.29 (m, 1H) 2.50 (m, 3H) 2.67 (m, 3H) 3.21 (m, 2H) 3.64 (q,J=6.23 Hz, 2H) 6.81 (m, 2H)6.89 (s, 2H)7.12 (m, 1H).

EXAMPLE 120

1-(4-(4-formylbutyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 98 using the compoundsprepared in Example 119, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.52 (ethyl acetate);

NMR (CDCl₃):d 1.68 (m, 5H) 2.00 (m, 1H) 2.08 (s, 3H) 2.17 (s, 3H) 2.30(m, 1H) 2.45 (m, 2H) 2.53 (m, 3H) 2.67 (m, 3H) 3.23 (m, 2H) 6.81 (m, 2H)6.89 (s, 2H) 7.13 (m, 1H) 9.77 (t, J=1.92 Hz, 1H).

EXAMPLE 121

1-(4-(4-carboxybutyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 120 (133 mg) int-butanol (3.0 ml) and water (0.8 ml) were added 2-methyl-2-butene (99mg), sodium dihydrogen phosphate (38 mg) and 85% sodium chlorite (99mg). The reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was diluted with ethyl acetate, washed with 1Nhydrochloric acid, water and brine, dried over anhydrous sodium sulfateand concentrated. The obtained residue was purified by preparative TLC(ethyl acetate) to give the compound of the present invention (108 mg)having the following physical data.

TLC:Rf 0.28 (ethyl acetate);

NMR (CDCl₃):d 1.66 (m, 5H) 1.99 (m, 1H) 2.08 (s, 3H) 2.17 (s, 3H) 2.31(m, 3H) 2.53 (m, 3H) 2.66 (m, 3H) 3.22 (m, 2H) 6.80 (m, 2H) 6.88 (s, 2H)7.11 (m, 1H).

EXAMPLE 122

(E)-1-(4-(2-(methoxycarbonyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 113 using 2-propenoic acidmethyl ester instead of 2-(3-butynyloxy)tetrahydro-2H-pyran, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.27 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.68 (m, 1H) 2.01 (m, 1H) 2.13 (s, 3H) 2.23 (s, 3H) 2.32(m, 1H) 2.51 (m, 1H) 2.68 (m, 3H) 3.21 (m, 2H) 3.80 (s, 3H) 6.37 (d,J=15.90 Hz, 1H) 6.81 (m, 2H) 7.12 (m, 1H) 7.25 (m, 2H) 7.60 (d, J=15.90Hz, 1H).

EXAMPLE 123

(E)-1-(4-(2-(carboxyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 122, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.43 (ethyl acetate:methanol=5:1);

NMR (DMSO-d₆):d 1.63 (m, 1H) 1.82 (m, 1H) 2.03 (s, 3H) 2.13 (s, 3H) 2.25(m, 1 H) 2.42 (m, 2H) 2.69 (m, 2H) 3.09 (m, 1H) 3.23 (m, 1H) 6.46 (d,J=16.10 Hz, 1H) 7.03 (m, 1H) 7.18 (m, 1H) 7.38 (m, 3H) 7.48 (d, J=16.10Hz, 1H) 12.36 (m, 1H).

EXAMPLE 124

1-(4-methoxycarbonyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 107 using the compoundprepared in Example 16(13), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.34 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 1.75 (m, 1H) 2.01 (m, 1H) 2.38 (m, 1H) 2.53 (m, 1H) 2.70(m, 3 H) 3.35 (m, 2H) 3.93 (s, 3H) 6.83 (m, 2H) 7.15 (m, 1H) 8.04 (m,2H).

EXAMPLE 125

1-(4-carboxyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 124, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.33 (ethyl acetate:methanol=4:1);

NMR (DMSO-d₆):d 1.63 (m, 1H) 1.87 (m, 1H) 2.30 (m, 1H) 2.45 (m, 2H) 2.72(m, 2H) 3.27 (m, 2H) 7.02 (m, 1H) 7.19 (m, 1H) 7.39 (m, 1H) 7.97 (m, 2H)13.64 (m, 1H).

EXAMPLE 126

1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 109 using the compoundprepared in Example 125, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.47 (ethyl acetate:methanol:triethylamine=7:2:1);

NMR (CDCl₃):d 1.73 (m, 1H) 2.00 (m, 1H) 2.27 (s, 6H) 2.38 (m, 1H) 2.53(m, 3 H) 2.70 (m, 3H) 3.35 (m, 2H) 3.49 (q, J=4.80 Hz, 2H) 6.84 (m, 3H)7.15 (m, 1H) 7.78 (m, 2H).

EXAMPLE 127

1-(4-(N,N-dimethylamino)methyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 70 using the compoundprepared in Example 7 and dimethylamine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.42 (ethyl acetate:methanol=19:1);

NMR (CDCl₃):d 1.72 (m, 1H) 1.98 (m, 1H) 2.25 (s, 6H) 2.36 (m, 1H) 2.51(m, 1 H) 2.69 (m, 3H) 3.35 (m, J=5.77 Hz, 4H) 6.82 (m, 2H) 7.15 (m, 1H)7.35 (m, 2H).

EXAMPLE 127(1)

1-(4-(4-methylpiperazin-1-ylmethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 127 using1-methylpiperazine instead of dimethylamine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.23 (ethyl acetate:triethylamine=9:1);

NMR (CDCl₃):d 1.73 (m, 1H) 1.98 (m, 1H) 2.30 (s, 3H) 2.45 (m, 10H) 2.65(m, 1 H) 2.72 (m, 2H) 3.34 (d, J=7.90 Hz, 2H) 3.43 (s, 2H) 6.82 (m, 2H)7.15 (m, 1H) 7.36 (m, 2H).

EXAMPLE 128

1-(4-(piperazin-1-yl)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 16(13) (500 mg) intoluene (5 ml) were added piperazine (766 mg) and sodium t-butoxide (160mg) under an atmosphere of argon. To the mixture was addeddichlorobis(tri-o-tolylphosphine)palladium(II) (44 mg). The reactionmixture was stirred at 100° C. for 4 hours. The reaction mixture wasdiluted with ethyl acetate, filtrated through Celite (proprietary name)and filtrated. The filtrate was concentrated. The obtained residue waspurified by column chromatography on silica gel (ethylacetate:methanol:triethylamine=1:0:0→10:2:1) to give the compound of thepresent invention (96 mg) having the following physical data.

TLC:Rf 0.20 (chloroform:methanol=4:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.95 (m, 1H) 2.33 (m, 1H) 2.49 (m, 1H) 2.67(m, 3 H) 2.99 (m, 4H) 3.15 (m, 4H) 3.33 (d, J=7.40 Hz, 2H) 6.83 (m, 4H)7.14 (m, 1H).

EXAMPLE 128(1)

1-(4-(4-methylpiperazin-1-yl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 128 using1-methylpiperazine instead of piperazine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.58 (chloroform:methanol=4:1);

NMR (CDCl₃):d 1.71 (m, 1H) 1.95 (m, 1H) 2.34 (m, 4H) 2.52 (m, 5H) 2.67(m, 3 H) 3.21 (m, 4H) 3.32 (d, J=7.70 Hz, 2H) 6.81 (m, 4H) 7.14 (m, 1H).

EXAMPLE 129

1-(4-(3-hydroxy-1-propynyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 118 using the compoundprepared in Example 16(3) and 2-propyn-1-ol, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.45 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.78 (t, J=6.30 Hz, 1H) 1.98 (m, 1H) 2.37 (m,1H) 2.51 (m, 1H) 2.69 (m, 3H) 3.33 (d, J=8.00 Hz, 2H) 4.47 (d, J=6.30Hz, 2H) 6.82 (m, 2H) 7.14 (m, 1H) 7.43 (m, 2H).

EXAMPLE 130

1-(4-(3-(N,N-dimethylamino)propyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 70→Reference Example 15using the compound prepared in Example 129, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.46 (ethyl acetate:methanol:triethylamine=8:1:1);

NMR (CDCl₃):d 1.74 (m, 3H) 1.97 (m, 1H) 2.23 (s, 6H) 2.29 (t, J=7.20 Hz,2H) 2.38 (m, 1H) 2.56 (m, 4H) 2.72 (m, 2H) 3.34 (d, J=7.70 Hz, 2H) 6.82(m, 2H) 7.14 (m, 1H) 7.20 (m, 2H).

EXAMPLE 131

1-(4-(3-aminopropyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-onehydrochloride

By the same procedure as described in Reference Example 15→Example 73using the compound prepared in Example 129, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.27 (chloroform:methanol:aqueous ammonia solution=90:10:1);

NMR (CDCl₃):d 1.72 (m, 1H) 1.98 (m, 3H) 2.46 (m, 7H) 2.92 (m, 2H) 3.33(d, J=7.42 Hz, 2H) 6.81 (m, 2H) 7.14 (m, 1H) 7.28 (m, 2H) 8.16 (m, 3H).

EXAMPLE 132

1-(4-(4-hydroxybut-1-ynyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 118 using thecompound prepared in Example 16(3) and 3-butyn-1-ol, the compound of thepresent invention having the following physical data was obtained.

TLC:Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.70 (m, 1H) 1.82 (t, J=6.20 Hz, 1H) 1.98 (m, 1H) 2.35 (m,1H) 2.50 (m, 1H) 2.68 (m, 5H) 3.33 (d, J=8.00 Hz, 2H) 3.79 (q, J=6.20Hz, 2H) 6.82 (m, 2H) 7.14 (m, 1H) 7.41 (m, 2H).

EXAMPLE 133

1-(4-(4-(N,N-dimethylamino)butyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 130 using the compoundprepared in Example 132, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.21 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.50 (m, 2H) 1.68 (m, 3H) 1.98 (m, 1H) 2.21 (s, 6H) 2.27(m, 2 H) 2.36 (m, 1H) 2.55 (m, 4H) 2.72 (m, 2H) 3.33 (d, J=7.69 Hz, 2H)6.81 (m, 2H) 7.16 (m, 3H).

EXAMPLE 134

(E)-1-(4-(2-(methyloxycarbonyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 122 using the compoundprepared in Example 16(3), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.50 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.73 (m, 1H) 2.00 (m, 1H) 2.38 (m, 1H) 2.53 (m, 1H) 2.66(m, 1 H) 2.73 (m, 2H) 3.35 (m, 2H) 3.82 (s, 3H) 6.41 (d, J=15.90 Hz, 1H)6.82 (m, 2H) 7.15 (m, 1H) 7.53 (m, 3H).

EXAMPLE 135

(E)-1-(4-(2-aminocarbonylvinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 108→Example 109 usingaqueous ammonia solution instead of the compound prepared in Example 134and 2-(N,N-dimethylamine)ethylamine, the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.54 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.74 (m, 1H) 2.00 (m, 1H) 2.38 (m, 1H) 2.54 (m, 1H) 2.71(m, 3 H) 3.36 (m, 2H) 5.46 (m, 1H) 6.04 (m, 1H) 6.24 (d, J=15.60 Hz, 1H)6.82 (m, 2H) 7.15 (m, 1H) 7.42 (m, 3H).

EXAMPLE 136

(E)-1-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

To a solution of the compound prepared in Example 135 (312 mg) indichloromethane (7.1 ml) were added pyridine (0.34 ml) and anhydroustrifluoromethanesulfonic acid (0.24 ml) at 0° C. under an atmosphere ofargon. The reaction mixture was stirred at room temperature for 20minutes. The reaction mixture was poured in 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with water andbrine, dried over anhydrous sodium sulfate and concentrated to give thecompound of the present invention (296 mg) having the following physicaldata.

TLC:Rf 0.52 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.74 (m, 1H) 1.99 (m, 1H) 2.37 (m, 1H) 2.53 (m, 1H) 2.70(m, 3 H) 3.33 (m, 2H) 5.89 (d, J=16.50 Hz, 1H) 6.82 (m, 2H) 7.15 (m, 1H)7.27 (d, J=16.50 Hz, 1H) 7.46 (m, 2H).

EXAMPLE 137

1-(4-(2-cyanoethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 136, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.38 (ethyl acetate:hexane);

NMR (CDCl₃):d 1.73 (m, 1H) 1.98 (m, 1H) 2.36 (m, 1H) 2.51 (m, 1H) 2.68(m, 5 H) 2.92 (t, J=7.40 Hz, 2H) 3.34 (m, 2H) 6.82 (m, 2H) 7.15 (m, 1H)7.26 (m, 2H).

EXAMPLE 138

1-(4-(2-methoxycarbonylethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 134, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.46 (ethyl acetate:hexane=2:1);

NMR (CDCl₃):d 1.71 (m, 1H) 1.97 (m, 1H) 2.35 (m, 1H) 2.51 (m, 1H) 2.63(m, 3 H) 2.72 (m, 2H) 2.90 (t, J=7.80 Hz, 2H) 3.33 (d, J=8.00 Hz, 2H)3.69 (s, 3H) 6.82 (m, 2H)7.15 (m, 1H)7.23 (m, 2H).

EXAMPLE 139

1-(4-(2-methylaminocarbonyl)ethyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 108→Example 109 using thecompound prepared in Example 138 and methylamine instead of2-(N,N-dimethylamine)ethylamine, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.41 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.74 (m, 1H) 1.98 (m, 1H) 2.37 (m, 3H) 2.52 (m, 1H) 2.65(m, 1 H) 2.72 (m, 2H) 2.78 (d, J=4.90 Hz, 3H) 2.92 (m, 2H) 3.33 (d,J=7.90 Hz, 2H) 5.61 (m, 1H)6.82 (m, 2H)7.14 (m, 1H)7.21 (s, 2H).

EXAMPLE 140

(3R,5R)-1-(4-methoxycarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 107 using the compoundprepared in Example 31(2), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.33 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.30 (d, J=7.14 Hz, 3H) 1.46 (m, J=12.64 Hz, 1H) 2.06 (m,1H) 2.15 (s, 3H) 2.22 (s, 3H) 2.36 (m, 1H) 2.52 (m, 1H) 2.66 (d, J=7.14Hz, 2H) 3.22 (d, J=11.26 Hz, 2H) 3.89 (s, 3H) 6.82 (m, 2H) 7.12 (m,J=6.59 Hz, 1H) 7.76 (s, 2 H).

EXAMPLE 141

(3R,5R)-1-(4-carboxy-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 140, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.15 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 1.32 (d, J=7.14 Hz, 3H) 1.48 (m, 1H) 2.07 (m, 1H) 2.15 (s,3H) 2.22 (s, 3H) 2.37 (m, 1H) 2.56 (m, 1H) 2.66 (d, J=7.14 Hz, 2H) 3.24(m, J=11.54 Hz, 2H)6.82 (m, 2H)7.11 (m, 1H)7.71 (s, 2H).

EXAMPLE 142

(3R,5R)-1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 109 using the compoundprepared in Example 141, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.15 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.30 (d, J=7.14 Hz, 3H) 1.46 (m, 1H) 2.14 (s, 3H) 2.22 (s,3H) 2.25 (m, J=15.93 Hz, 1H) 2.27 (s, 6H) 2.51 (m, 4H) 2.65 (d, J=7.14Hz, 2H) 3.18 (m, 2H) 3.50 (m, J=5.77 Hz, 2H) 6.79 (m, 3H) 7.11 (m, 1H)7.47 (s, 2H).

EXAMPLE 143

(3R,5R)-1-(4-(3-(N,N-dimethylamino)-1-propynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 118 usingN,N-dimethyl-2-propynylamine and the compound prepared in Example 32(2)instead of 4-pentyn-1-ol, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.15 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.30 (d, J=7.14 Hz, 3H) 1.45 (m, J=12.64 Hz, 1H) 2.06 (m,1H) 2.06 (s, 3H) 2.14 (s, 3H) 2.33 (m, J=10.16 Hz, 1H) 2.34 (s, 6H) 2.52(m, 1H) 2.65 (d, J=7.14 Hz, 2H) 3.20 (m, J=11.54 Hz, 2H) 3.45 (s, 2H)6.81 (m, 2H) 7.11 (m, J=6.32 Hz, 1H) 7.16 (s, 2H).

EXAMPLE 144

(3R,5R)-1-(4-(3-(N,N-dimethylamino)propynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 143, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃):d 1.30 (d, J=6.87 Hz, 3H) 1.45 (m, 1H) 1.75 (m, 2H) 2.07 (m,1H) 2.07 (s, 3H) 2.14 (s, 3H) 2.23 (s, 6H) 2.30 (m, 3H) 2.53 (m, 3H)2.64 (d, J=7.14 Hz, 2H) 3.22 (m, J=11.26 Hz, 2H) 6.81 (m, 2H) 6.89 (s,2H) 7.11 (m, 1H).

EXAMPLE 145

1-(4-carboxyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

By the same procedure as described in Example 107→Example 108 using thecompound prepared in Example 20, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.45 (ethyl acetate:methanol=19:1);

NMR (DMSO-d₆):d 2.10 (s, 3H) 2.20 (s, 3H) 2.35 (m, 1H) 2.71 (d, J=7.14Hz, 2H) 3.12 (m, 4H) 6.58 (m, J=3.30 Hz, 1H) 7.03 (m, 1H) 7.19 (m, 1H)7.39 (m, 1H) 7.63 (s, 2H).

EXAMPLE 146

1-(4-t-butyloxycarbonylamino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

By the same procedure as described in Example 111 using the compoundprepared in Example 145, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.43 (ethyl acetate);

NMR (CDCl₃):d 1.50 (s, 9H) 2.14 (s, 3H) 2.23 (s, 3H) 2.50 (m, 1H) 2.73(m, 2H) 3.26 (m, 4H) 4.77 (d, J=1.10 Hz, 1H) 6.40 (s, 1H) 6.82 (m, 2H)7.12 (m, 3H).

EXAMPLE 147

1-(4-amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

By the same procedure as described in Reference Example 31 using thecompound prepared in Example 146, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.43 (ethyl acetate);

NMR (CDCl₃):d 2.08 (s, 3H) 2.17 (s, 3H) 2.49 (m, J=2.75 Hz, 1H) 2.72 (m,2H) 3.26 (m, 4H) 3.55 (s, 2H) 4.92 (s, 1H) 6.38 (s, 2H) 6.81 (m, 2H)7.13 (m, 1H).

EXAMPLE 148

1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one

TLC:Rf 0.45 (ethyl acetate:methanol:triethylamine=8:1:1);

NMR (CDCl₃):d 2.22 (s, 3H) 2.27 (s, 6H) 2.31 (s, 3H) 2.51 (m, 3H) 2.74(m, J=6.87 Hz, 2H) 3.28 (m, 4H) 3.50 (m, 2H) 4.84 (m, J=3.85 Hz, 1H)6.73 (m, 1H) 6.83 (m, 2H) 7.14 (m, J=6.59 Hz, 1H) 7.46 (s, 2H).

EXAMPLE 149

1-(2,6-dimethylphenyl)-5-(2-methoxycarbonylbenzyl)piperidin-2-one

By the same procedure as described in Example 107 using the compoundprepared in Example 16(5), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.32 (ethyl acetate:toluene=3:1);

NMR (CDCl₃):d 1.66 (m, 1H) 2.04 (m, 1H) 2.11 (s, 3H) 2.23 (s, 3H) 2.33(m, 1H) 2.46 (m, 1H) 2.66 (m, 1H) 2.94 (m, 1H) 3.12 (m, 1H) 3.28 (m, 2H)3.88 (m, 3H) 7.09 (m, 3H) 7.27 (m, 2H) 7.43 (m, 1H) 7.96 (dd, J=7.97,1.37 Hz, 1H).

EXAMPLE 150

1-(2,6-dimethylphenyl)-5-(2-carboxybenzyl)piperidin-2-one

By the same procedure as described in Example 36 using the compoundprepared in Example 149, the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.36 (ethyl acetate:methanol=5:1);

NMR (DMSO-d₆):d 1.64 (m, 1H) 1.83 (m, 1H) 1.99 (m, 3H) 2.13 (m, 3H) 2.32(m, 2H) 2.99 (m, 3H) 3.29 (m, 2H) 7.07 (s, 3H) 7.30 (m, 2H) 7.46 (m, 1H)7.82 (d, J=8.06 Hz, 1H) 12.93 (m, 1H).

EXAMPLE 151

1-(2,6-dimethylphenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one

By the same procedure as described in Example 122 using the compoundprepared in Example 16(5), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.35 (ethyl acetate);

NMR (CDCl₃):d 1.65 (m, 1H) 2.00 (m, 4H) 2.21 (m, 4H) 2.46 (m, 1H) 2.66(m, 1 H) 2.84 (m, 2H) 3.25 (m, 2H) 3.82 (s, 3H) 6.39 (d, J=15.66 Hz, 1H)7.04 (m, 2H) 7.17 (m, 1H) 7.30 (m, 2H) 7.59 (m, 2H) 7.99 (d, J=15.66 Hz,1H).

EXAMPLE 152

(3R,5R)-1-(4-amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 10 using the compoundprepared in Example 31(1), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.73 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 1.28 (d, J=7.14 Hz, 3H) 1.46 (m, J=12.36 Hz, 1H) 1.99 (m,1H) 2.43 (m, 2H) 2.65 (d, J=7.42 Hz, 2H) 3.31 (m, J=10.71 Hz, 2H) 3.85(s, 2H) 6.61 (s, 2H) 6.81 (m, 2H)7.12 (m, 1H).

EXAMPLE 153

(3R,5R)-1-(4-(t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Reference Example 39 using thecompound prepared in Example 152, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.52 (hexane:ethyl acetate=2:1);

NMR (CDCl₃):d 1.32 (d, J=6.87 Hz, 3H) 1.50 (m, 1H) 1.48 (s, 9H) 2.05 (m,1H) 2.37 (m, 1H) 2.53 (m, 1H) 2.65 (d, J=7.42 Hz, 2H) 3.27 (m, 2H) 6.82(m, 2H) 7.10 (m, 2H) 7.51 (m, J=2.20 Hz, 1H) 7.75 (s, 1H).

EXAMPLE 154

(3R,5R)-1-(4-(2-(N,N-dimethylamino)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one

By the same procedure as described in Example 57→Example 58 using thecompound prepared in Example 153, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.02 (ethyl acetate:methanol=9:1);

NMR (CDCl₃):d 1.28 (d, J=7.14 Hz, 3H) 1.46 (m, 1H) 1.98 (m, 1H) 2.23 (s,6H) 2.53 (m, 4H) 2.64 (d, J=7.69 Hz, 2H) 3.06 (m, J=6.32 Hz, 2H) 3.29(m, 2H) 4.60 (m, 1H)6.56 (s, 2H)6.81 (m, 2H)7.12 (m, 1H).

EXAMPLE 155

1-(2,6-dimethylphenyl)-5-(3-phenylpropyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 18, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.45 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.32-7.22 (m, 3H), 7.21-7.06 (m, 5H), 3.28 (ddd, J=, 12.0,5.1, 1.8 Hz, 1H), 3.12 (dd, J=12.0, 10.2 Hz, 1H), 2.70-2.59 (m, 3H),2.51 (ddd, J=17.4, 11.1, 5.7 Hz, 1H), 2.18 (s, 3H), 2.17 (s, 3H),2.07-1.92 (m, 2H), 1.78-1.55 (m, 3H), 1.49-1.36 (m, 2H).

EXAMPLES 156

(3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-hydropiperidin-2-one(compound 1) and(3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-hydropiperidin-2-one(compound 2)

To a solution of the compound prepared in Example 1(1) (315 mg) intetrahydrofuran (5 ml) was added lithium bis(trimethylsilyl)amide (1.0Msolution in tetrahydrofuran, 900 μl) at −78° C. under an atmosphere ofargon. The mixture was stirred at same temperature for 30 minutes. Tothe mixture was added a solution of3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (245 mg) in tetrahydrofuran(3 ml) at −70° C. The reaction mixture was stirred at −70° C. for 6hours. A saturated aqueous ammonium chloride solution was added to thereaction mixture, which was extracted with ethyl acetate. The extractwas washed water and brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=3:2) to give the compound (1) (29mg) and the compound (2) (37 mg) of the present invention having thefollowing physical data respectively.

EXAMPLE 156(1)

TLC:Rf 0.56 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 1.78 (m, 1H) 2.36 (m, 1H) 2.52 (m, 1H) 2.75 (m, 2H) 3.39(m, 2 H) 3.50 (s, 1H) 4.21 (dd, J=11.81, 5.77 Hz, 1H) 6.83 (m, 2H) 7.14(m, 1H) 7.26 (m, 1H)7.40 (m, 2H).

EXAMPLE 156(2)

TLC:Rf 0.51 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 2.11 (m, 2H) 2.76 (m, 3H) 3.43 (m, 3H) 4.44 (m, 1H) 6.83(m, 2 H) 7.21 (m, 2H) 7.39 (d, J=7.97 Hz, 2H).

EXAMPLES 157

(3RS,5RS)-1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one(compound 1) and(3RS,5SR)-1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one(compound 2)

By the same procedure as described in Example 14 using the compoundprepared in Example 5, the compound (1) and the compound (2) of thepresent invention having the following physical data were obtainedrespectively.

EXAMPLE 157(1)

TLC:Rf 0.53 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.18-7.02 (m, 4H), 6.88-6.75 (m, 2H), 3.23 (dd, J=12.0,11.1 Hz, 1H), 3.16 (ddd, J=12.0, 5.1, 1.8 Hz, 1H), 2.65 (d, J=7.2 Hz,2H), 2.60-2.45 (m, 1H), 2.45-2.25 (m, 1H), 2.18 (s, 3H), 2.15-2.00 (m,4H), 1.46 (ddd, J=12.6, 12.3, 12.3 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H).

EXAMPLE 157(2)

TLC:Rf 0.40 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 7.18-7.02 (m, 4H), 6.88-6.75 (m, 2H), 3.30-3.15 (m, 2H),2.82-2.60 (m, 3H), 2.60-2.40 (m, 1H), 2.20 (s, 3H), 2.10 (s, 3H), 1.88(ddd, J=13.5, 10.2, 6.6 Hz, 1H), 1.77 (dddd, J=13.5, 3.9, 3.9, 1.5 Hz,1H), 1.34 (d, J=7.2 Hz, 3H).

EXAMPLE 158

(5S)-1-(2,6-dimethylphenyl)-5-(methyl(2,4-difluorophenylsulfonyl)amino)piperidin-2-one

By the same procedure as described in Example 51 using the compoundprepared in Example 34, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.40 (hexane:ethyl acetate=1:4);

NMR (CDCl₃):d 2.17 (s, 3H) 2.23 (m, 1H) 2.24 (s, 3H) 2.63 (m, 4H) 2.66(s, 3H) 3.51 (m, J=12.64, 10.16 Hz, 1H) 4.14 (m, 1H) 6.94 (m, 2H) 7.13(m, 3H) 7.78 (m, 1H).

EXAMPLE 158(1)

(5S)-1-(2,6-dimethylphenyl)-5-((2-hydroxyethyl)(2,4-difluorophenylsulfonyl)amino)piperidin-2-one

By the same procedure as described in Example 51 using 2-bromoethanolinstead of methyl iodide, and the compound prepared in Example 34, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.22 (hexane:ethyl acetate=1:4);

NMR (CDCl₃):d 1.84 (m, 1H) 2.17 (s, 3H) 2.22 (s, 3H) 2.54 (m, 4H) 2.92(dd, J=14.01, 3.02 Hz, 1H) 3.06 (m, 1H) 3.23 (m, 1H) 3.66 (m, 3H) 4.25(m, 1H) 6.95 (m, 2H)7.12 (m, 3H)7.77 (m, 1H).

EXAMPLE 159

1-(4-(N-methylcarbonyl-N-methylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one

By the same procedure as described in Example 13 using the compoundprepared in Example 12(1), the compound of the present invention havingthe following physical data was obtained.

TLC:Rf 0.33 (ethyl acetate);

NMR (CDCl₃):d 1.74 (m, 1H) 2.04 (m, 4H) 2.39 (m, 1H) 2.53 (m, 1H) 2.66(dd, J=5.77, 3.57 Hz, 1H) 2.73 (d, J=7.14 Hz, 2H) 3.26 (s, 3H) 3.36 (d,J=7.14 Hz, 2H) 6.83 (m, 2H) 7.16 (m, 1H) 7.26 (m, 2H).

EXAMPLE 160

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methyltetrahydropyrimidin-2(1H)-one

By the same procedure as described in Example 13 using the compoundprepared in Example 19, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.53 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 7.40-7.34 (m, 2H), 7.21-7.12 (m, 2H), 6.88-6.77 (m, 2H),3.47-3.37 (m, 2H), 3.32 (m, 1H), 3.20 (dd, J=12.0, 8.7 Hz, 1H), 2.99 (s,3H), 2.89-2.71 (m, 2H), 2.63 (m, 1H).

EXAMPLE 161

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperazin-2-one

By the same procedure as described in Example 114 using the compoundprepared in Example 19, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.19 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 2.85 (m, 2H) 3.36 (m, 1H) 3.50 (m, 2H) 3.68 (d, J=17.58Hz, 1H) 3.81 (d, J=17.58 Hz, 1H) 6.85 (m, 2H) 7.23 (m, 2H) 7.40 (m, 2H).

EXAMPLE 162

1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-4-methylpiperazin-2-onehydrochloride

By the same procedure as described in Example 47→Reference Example 31using the compound prepared in Example 161 and formaldehyde, thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.31 (ethyl acetate:hexane=4:1);

NMR (CD₃OD):d 3.18 (m, 4H) 3.50 (dd, J=14.28, 4.40 Hz, 1H) 3.60 (dd,J=14.01, 4.12 Hz, 1H) 3.95 (dd, J=14.01, 9.61 Hz, 1H) 4.34 (m, 3H) 7.03(m, 2H) 7.49 (m, 4 H).

EXAMPLE 163

1-(2,6-dichlorophenyl)-5-(2,4-difluorophenylcarbonyl)piperidin-2-one

By the same procedure as described in Example 98 using the compoundprepared in Example 24, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.33 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.94 (m, 1H), 7.42-7.38 (m, 2H), 7.23 (m, 1H), 7.01 (m,1H), 6.94 (m, 1H), 3.99-3.79 (m, 2H), 3.62 (m, 1H), 2.80 (ddd, J=17.7,5.7, 3.9 Hz, 1H), 2.69 (m, ddd, J=17.7, 11.1, 6.3 Hz, 1H), 2.33 (m, 1H),2.15 (m, 1H).

EXAMPLE 164

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-hydroxyethyl)piperidin-2-one

To a solution of the compound prepared in Example 163 (300 mg) intetrahydrofuran (5 ml) was added methylmagnesium bromide (0.93M solutionin tetrahydrofuran, 1.85 ml) at 0° C. under an atmosphere of argon. Thereaction mixture was stirred at room temperature for 3 hours. Asaturated aqueous ammonium chloride solution was added to the reactionmixture, which was extracted with ethyl acetate. The extract was washedwater and brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=7:3→3:2) to give the compound (1)(125 mg) and the compound (2) (85 mg) of the present invention havingthe following physical data respectively.

EXAMPLE 164(1)

TLC:Rf 0.50 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.58 (m, 1H), 7.43-7.37 (m, 2H), 7.22 (t, J=7.8 Hz, 1H),6.94-6.78 (m, 2H), 3.71 (t, J=11.1 Hz, 1H), 3.48 (ddd, J=11.1, 5.4, 2.1Hz, 1H), 2.69-2.56 (m, 2H), 2.42 (ddd, J=18.3, 11.7, 6.0 Hz, 1H), 1.92(d, J=1.2 Hz, 1H), 1.81 (m, 1H), 1.66 (d, J=1.2 Hz, 3H), 1.61 (m, 1H).

EXAMPLE 164(2)

TLC:Rf 0.32 (ethyl acetate:hexane=3:2);

NMR (CDCl₃):d 7.56 (m, 1H), 7.36-7.28 (m, 2H), 7.16 (t, J=7.8 Hz, 1H),6.88-6.77 (m, 2H), 3.47 (t, J=11.4 Hz, 1H), 2.87-2.63 (m, 3H), 2.58(ddd, J=18.0, 11.7, 6.3 Hz, 1H), 2.16 (m, 1H), 1.99 (m, 1H), 1.88 (d,J=1.2 Hz, 1H), 1.71 (d, J=1.2 Hz, 3H).

EXAMPLE 165

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)vinyl)piperidin-2-one

To a solution of the compound prepared in Example 164(1) (75 mg) intoluene (3 ml) was added p-toluenesulfonic acid (7 mg). The reactionmixture was stirred at 130° C. for 12 hours. The reaction mixture wasdiluted with ethyl acetate, washed with a saturated aqueous sodiumhydrogen carbonate solution, water and brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=7:3) to givethe compound of the present invention (70 mg) having the followingphysical data.

TLC:Rf 0.45 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.38 (d, J=8.1 Hz, 2H), 7.23-7.14 (m, 2H), 6.90-6.78 (m,2H), 5.37 (s, 1H), 5.26 (s, 1H), 3.51 (t, J=11.1 Hz, 1H), 3.40 (ddd,J=11.1, 5.1, 2.1 Hz, 1H), 3.19 (m, 1H), 2.76 (ddd, J=18.0, 5.7, 2.7 Hz,1H), 2.62 (ddd, J=18.0, 11.4, 6.3 Hz, 1H), 2.18 (m, 1H), 1.93 (m, 1H).

EXAMPLE 166

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)ethyl)piperidin-2-one

By the same procedure as described in Reference Example 15 using thecompound prepared in Example 165, the compound of the present inventionhaving the following physical data was obtained.

TLC:Rf 0.47 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 7.43-7.38 (m, 2H), 7.25-7.16 (m, 2H), 6.92-6.77 (m, 2H),3.56 (ddd, J=11.7, 5.4, 2.1 Hz, 1H), 3.40 (t, J=11.7 Hz, 1H), 3.03 (m,1H), 2.59 (ddd, J=17.7, 5.4, 3.6 Hz, 1H), 2.41 (ddd, J=17.7, 11.1, 6.3Hz, 1H), 2.25 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.29 (d, J=6.9 Hz,3H).

EXAMPLE 167

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)1-hydroxyiminomethyl)piperidin-2-one

To a solution of the compound prepared in Example 163 (107 mg) inpyridine (3 ml) was added hydroxylamine hydrochloride (58 mg). Thereaction mixture was stirre at 60° C. for 8 hours. The reaction mixturewas diluted with ethyl acetate, washed with 2N hydrochloric acid, water,a saturated aqueous sodium hydrogen carbonate solution, water and brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was washed with isopropyl ether to give the compound of thepresent invention (96 mg) having the following physical data.

TLC:Rf 0.27 (ethyl acetate:hexane=1:1);

NMR (CDCl₃):d 8.12 and 7.51 (s and s, 1H), 7.42-7.33 (m, 2H), 7.29-7.17(m, 2H), 7.01-6.83 (m, 2H), 4.00-3.16 (m, 3H), 2.81-2.50 (m, 2H),2.23-1.91 (m, 2H).

EXAMPLE 168

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-methoxymethyl)piperidin-2-one

By the same procedure as described in Example 13 using the compoundprepared in Example 24, the compound of the present invention having thefollowing physical data was obtained.

TLC:Rf 0.31 (ethyl acetate:hexane=2:3);

NMR (CDCl₃):d 7.40-7.32 (m, 3H), 7.19 (t, J=8.4 Hz, 1H), 7.94 (m, 1H),6.81 (m, 1H), 4.43 (d, J=6.9 Hz, 1H), 3.45 (t, J=11.4 Hz, 1H), 3.23 (s,3H), 3.10 (ddd, J=11.4, 5.1, 1.8 Hz, 1H), 2.70 (ddd, J=17.7, 5.4, 3.0Hz, 1H), 2.57-2.36 (m, 2H), 2.20 (m, 1H), 1.82 (m, 1H).

EXAMPLE 169

1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-chloromethyl)piperidin-2-one

To a solution of the compound prepared in Example 24 (12 mg) in toluene(1 ml) was added thionyl chloride (10 μl). The reaction mixture wasstirred at 100° C. for 30 minutes. The reaction mixture was concentratedto give the compound of the present invention (12 mg) having thefollowing physical data.

TLC:Rf 0.72 (hexane:ethyl acetate=2:3);

NMR (CDCl₃):d 1.71 (m, 1H) 1.92 (m, 1H) 2.62 (m, 3H) 3.16 and 3.62 (mand dd J=11.81, 9.43 Hz, 1H) 3.34 and 3.38 (t and m, J=11.17 Hz, 1H)5.15 (d and d, J=9.34 and J=8.42 Hz, 1H) 6.90 (m, 2H)7.37 (m, 4H).

EXAMPLE 170

(5E)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzylidene)piperidin-2-one

To a solution of the compound prepared in Example 169 (12 mg) in ethanol(2 ml) was added potassium hydroxide (110 mg). The reactioin mixture wasstirred at 80° C. for 3 hours. To the reaction mixture was 1Nhydrochloric acid to neutralize. The reaction mixture was concentrated,diluted with ethyl acetate, washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The reaction mixture waspurified by preparative TLC (toluene:ethyl acetate=4:1, twice) to givethe compound of the present invention (1.9 mg) having the followingphysical data.

TLC:Rf 0.46 (ethyl acetate:toluene=3:7);

NMR (CDCl₃):d 2.66 (m, 2H) 2.78 (m, 2H) 4.30 (d, J=1.46 Hz, 2H) 6.44 (s,1H) 6.88 (m, 2H) 7.25 (m, 2H) 7.42 (m, 2H).

EXAMPLE 171

(5E)-1′-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzylidene)piperidin-2-one

By the same procedure as described in Example 169→Example 170 using thecompound prepared in Example 25(4), the compound of the presentinvention having the following physical data was obtained.

TLC:Rf 0.40 (ethyl acetate:hexane=3:7);

NMR (CDCl₃):d 2.64 (m, 2H) 2.77 (m, 2H) 4.27 (d, J=1.28 Hz, 2H) 6.44 (s,1H) 6.88 (m, 2H) 7.24 (m, 1H) 7.59 (s, 2H).

EXAMPLE 172

1-(4-amino-2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)1-hydroxyiminomethyl)piperidin-2-one

By the same procedure as described in Example 163→Reference Example31→Example 168 using the compound prepared in Example 25(1), thecompound of the present invention having the following physical data wasobtained.

TLC:Rf 0.35 (ethyl acetate:hexane=4:1);

NMR (CDCl₃):d 2.07 (m, 2H) 2.65 (m, 2H) 3.80-3.11 (m, 3H) 3.91 (s, 2H)6.60 (m, 2H) 6.92 (m, 2H) 7.23 (m, 1H) 7.68 and 8.23 (s and s, 1H).

REFERENCE EXAMPLE 42

1-(2,6-dichlorophenyl)piperidin-2,5-dione

By the same procedure as described in Example 98 using the compoundprepared in Reference Example 12, the title compound having thefollowing physical data was obtained.

TLC:Rf 0.40 (hexane:ethyl acetate=1:1);

NMR (CDCl₃):d 2.91 (m, 4H) 4.16 (s, 2H) 7.28 (m, 1H) 7.43 (m, 2H).

EXAMPLE 173

1-(2,6-dichlorophenyl)-5-(2,4-difluorophenylamino)piperidin-2-one

By the same procedure as described in Example 47 using the compoundprepared in Reference Example 42 and 2,4-difluoroaniline, the compoundof the present invention having the following physical data wasobtained.

TLC:Rf 0.33 (ethyl acetate:toluene=1:4);

NMR (CDCl₃):d 2.12 (m, 1H) 2.26 (m, 1H) 2.73 (m, 2H) 3.42 (dd, J=11.95,6.18 Hz, 1H) 3.85 (m, 1H) 4.00 (m, 2H) 6.76 (m, 3H) 7.22 (m, 1H) 7.39(m, 2H).

FORMULATION EXAMPLE 1

The following components were admixed in a conventional method, punchedout to give 100 tablets each containing 50 mg of active ingredient.1-(2,6-di chlorophenyl)-5-(2,4-difluorobenzyl)piperidine-2-one (5.0 g)carboxymethylcellulose (disintegrant) (0.2 g) magnesium stearate(lubricant) (0.1 g) microcrystalline cellulose (4.7 g)

FORMULATION EXAMPLE 2

The following components were admixed in a conventional method. Thesolution was sterilized in a conventional method, filled in ampoules 5ml each and freeze-dried in a conventional method to give 100 ampouleseach containing 20 mg of active ingredient.

-   1-(2,6-di chlorophenyl)-5-(2,4-difluorobenzyl)piperidine-2-one (2.0    g)-   mannitol (20 g)-   distilled water (1000 ml)

1. A piperidin-2-one derivative compound represented by formula (I):

wherein ring A represents a C5-10 mono- or bi-carbocyclic ring, or a 5-to 10-membered mono- or bi-heterocyclic ring having 1 to 5 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom; R¹ represents (1)C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) a halogen atom, (5)—OR⁴, (6) —NR⁵R⁶, (7) —NR⁷COR⁸, (8) —CONR⁹R¹⁰, (9) —COOR¹¹, (10)—SO₂NR¹²R¹³, (11) —NR¹⁴SO₂R¹⁵, (12) —SR¹⁶, (13) —S(O)R¹⁷, (14) —SO₂R¹⁸,(15) —NR²²COOR²³, (16) —NR²⁴CONR²⁵R²⁶, (17) —COR²⁷, (18) —NO₂, (19) —CN,(20) —CF₃, (21) —OCF₃, (22) Cyc1, or (23) C1-8 alkyl, C2-8 alkenyl orC2-8 alkynyl substituted with 1 to 5 substituent(s) selected from thegroup consisting of (a) a halogen atom, (b) —OR⁴, (c) —NR⁵R⁶, (d)—NR⁷COR⁸, (e) —CONR⁹R¹⁰, (f) —COOR¹¹, (g) —SO₂NR¹²R¹³, (h) —NR¹⁴SO₂R¹⁵,(i) —SR¹⁶, (j) —S(O)R¹⁷, (k) —SO₂R¹⁸, (l) —NR²²COOR²³, (m)—NR²⁴CONR²⁵R²⁶, (n) —COR²⁷, (o) —NO₂, (p) —CN, (q) —CF₃, (r) —OCF₃, and(s) Cyc1; R⁴-R¹⁸ or R²²-R²⁷ each independently represents (1) a hydrogenatom, (2) C1-8 alkyl, (3) Cyc1, or (4) C1-8 alkyl substituted with 1 to5 substituent(s) selected from the group consisting of (a) —OR²⁸, (b)—NR²⁹R³⁰, (c) —NR³¹COR³², (d) —CONR³³R³⁴, (e) —COOR³⁵, (f) —SO₂NR³⁶R³⁷,(g) —NR³⁸SO₂R³⁹, (h) —CONR⁴⁰NR⁴¹R⁴², (i) —CONR⁴³OR⁴⁴, and (j) Cyc1,R²⁸-R⁴⁴ each independently represents (1) a hydrogen atom, (2) C1-8alkyl, (3) Cyc1, or (4) C1-8 alkyl substituted with 1 to 5substituent(s) selected from the group consisting of —OR⁴⁵, —NR⁴⁶R⁴⁷,and Cyc1; R⁴⁵-R⁴⁷ each independently represents a hydrogen atom, C1-8alkyl, Cyc1, or C1-8 alkyl substituted with Cyc1; Cyc1 represents aC5-10 mono- or bi-carbocyclic ring or a 5- to 10-membered mono- orbi-heterocyclic ring having 1 to 5 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or a sulfur atom, in which the carbocyclic ring or theheterocyclic ring may be substituted with 1 to 5 of R⁴⁸; R⁴⁸ represents(1) C1-8 alkyl, (2) a halogen atom, (3) —NO₂, (4) —CN, (5) —OR⁴⁹, (6)—NR⁵⁰R⁵¹, (7) —COOR⁵², (8) —COR⁵³, (9) —CONR⁵⁴R⁵⁵, (10) —NR⁵⁶COR⁵⁷, (11)—SO₂NR⁵⁸R⁵⁹, (12) —NR⁶⁰SO₂R⁶¹, (13) —SR⁶², (14) —SO₂R⁶³, (15) oxo, (16)—CF₃, (17) —OCF₃, or (18) C1-8 alkyl substituted with 1 to 5substituent(s) selected from the group consisting of (a) a halogen atom,(b) —NO₂, (c) —CN, (d) —OR⁴⁹, (e) —NR⁵⁰R⁵¹, (f) —COOR⁵², (g) —COR⁵³, (h)—CONR⁵⁴R⁵⁵, (i) —NR⁵⁶COR⁵⁷, (j) —SO₂NR⁵⁸R⁵⁹, (k) —NR⁶⁰SO₂R⁶¹, (l) —SR⁶²,(m) —SO₂R⁶³ (n) oxo, (o) —CF₃, and (p) —OCF₃; R⁴⁹-R⁶³ each independentlyrepresents, a hydrogen atom, C1-8 alkyl, phenyl, or C1-8 alkylsubstituted with phenyl; R² represents (1) C1-8 alkyl, (2) —OR²⁰, (3)—NR⁶⁴R⁶⁵, (4) —COOR⁶⁶, (5) —CONR⁶⁷R⁶⁸, (6) —NR⁶⁹COR⁷⁰, (7) —SO₂R⁷¹, (8)—SO₂NR⁷²R⁷³, (9) —NR⁷⁴SO₂R⁷⁵, (10) —NR⁷⁶COOR⁷⁷, (11) Cyc2, or (12) C1-8alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to 5substituent(s) selected from the group consisting of (a) —OR²⁰, (b)—NR⁶⁴R⁶⁵, (c) —COOR⁶⁶, (d) —CONR⁶⁷R⁶⁸, (e) —NR⁶⁹COR⁷⁰, (f) —SO₂R⁷¹, (g)—SO₂NR⁷²R⁷³, (h) —NR⁷⁴SO₂R⁷⁵, (i) —NR⁷⁶COOR⁷⁷, and (j) Cyc2; R²⁰ andR⁶⁴-R⁷⁷ each independently represents (1) a hydrogen atom, (2) C1-8alkyl, (3) Cyc2 or (4) C1-8 alkyl substituted with Cyc2; Cyc2 representsa C5-6 monocarbocyclic ring, or a 5- to 6-membered monoheterocyclic ringhaving 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or a sulfuratom, in which the carbocyclic ring or the heterocyclic ring may besubstituted with 1 to 5 substituent(s) selected from the groupconsisting of C1-8 alkyl, C1-8 alkoxy, a halogen atom, —CF₃ and —OCF₃; Gor J each independently represents, a carbon atom, a nitrogen atom, anoxygen atom, or a sulfur atom; E represents C1-4 alkylene, C2-4alkenylene, —O—, —S—, —NR²¹—,

, —NR⁷⁹SO₂— or —SO₂NR⁸⁰—, in which the C1-4 alkylene may be substitutedwith 1 to 5 of C1-8 alkyl, C1-8 alkoxy, a halogen atom, or hydroxyl; R²¹and R⁷⁸-R⁸⁰ each independently represents (1) a hydrogen atom, (2) C1-8alkyl, (3) Cyc3, (4) C1-8 alkyl substituted with 1 to 5 of Cyc3 orhydroxyl; Cyc3 represents a C5-6 monocarbocyclic ring, or a 5- to6-membered monoheterocyclic ring having 1 to 4 nitrogen atom(s), 1 to 2oxygen atom(s) and/or a sulfur atom, in which the carbocyclic ring orthe heterocyclic ring may be substituted with 1 to 5 of C1-8 alkyl, C1-8alkoxy, a halogen atom, —CF₃ or —OCF₃; ring B represents a C5-10 mono-or bi-carbocyclic ring, or a 5- to 10-membered mono- or bi-heterocyclicring having 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or asulfur atom; R³ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8alkynyl, (4) a halogen atom, (5) —OR⁸¹, (6) —NR⁸²R⁸³, (7) —NR⁸⁴COR⁸⁵,(8) —CONR⁸⁶R⁸⁷, (9) —COOR⁸⁸, (10) —SO₂NR⁸⁹R⁹⁰, (11) —NR⁹¹SO₂R⁹², (12)—SR⁹³, (13) —S(O)R⁹⁴, (14) —SO₂R⁹⁵, (15) —NR⁹⁶COOR⁹⁷, (16)—NR⁹⁸CONR⁹⁹R¹⁰⁰, (17) —OCONR¹⁰¹R¹⁰², (18) —NO₂, (19) —CN, (20) —CF₃,(21) —OCF₃, (22) Cyc4, or (23) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with 1 to 5 substituent(s) selected from the groupconsisting of (a) a halogen atom, (b) —OR⁸¹, (c) —NR⁸²R⁸³, (d)—NR⁸⁴COR⁸⁵, (e) —CONR⁸⁶R⁸⁷, (f) —COOR⁸⁸, (g) —SO₂NR⁸⁹R⁹⁰, (h)—NR⁹¹SO₂R⁹², (i) —SR⁹³, (j) —S(O)R⁹⁴, (k) —SO₂R⁹⁵, (l) —NR⁹⁶COR⁹⁷, (m)—NR⁹⁸CONR⁹⁹R¹⁰⁰, (n) —OCONR¹⁰¹R¹⁰², (o) —NO₂, (p) —CN, (q) —CF₃, (r)—OCF₃, and (s) Cyc4; R⁸¹-R¹⁰² each independently represents (1) ahydrogen atom, (2) C1-8 alkyl, (3) Cyc4 or (4) C1-8 alkyl substitutedwith 1 to 5 substituent(s) selected from the group consisting of Cyc4,—OR¹⁰³, —CONR¹⁰⁴R¹⁰⁵, and —COOR¹⁰⁶; R¹⁰³-R¹⁰⁶ each independentlyrepresents, (1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc4 or (4) C1-8alkyl substituted with 1 to 5 substituent(s) selected from Cyc4 and—OR¹⁰⁷; R¹⁰⁷ represents (1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc4 or(4) C1-8 alkyl substituted with Cyc4; Cyc4 is a C5-10 mono- orbi-carbocyclic ring, or a 5- to 10-membered mono- or bi-heterocyclicring having 1 to 5 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or asulfur atom, in which the carbocyclic ring or the heterocyclic ring maybe substituted with 1 to 5 of C1-8 alkyl, C1-8 alkoxy, a halogen atom,—CF₃ or —OCF₃; m represents 0 or an integer of 1 to 5; n represents 0 oran integer of 1 to 7; i represents 0 or an integer of 1 to 12, wherein(1) when m is 2 or more, R¹ is the same or different, (2) when n is 2 ormore, R² is the same or different, (3) when i is 2 or more, R³ is thesame or different, (4) when E is C1-4 alkylene,

is a single bond or a double bond, (5) when E is other than C1-4alkylene,

is a single bond, or a non-toxic salt thereof.
 2. The compound accordingto claim 1, wherein G is a carbon atom, and J is a carbon atom, or anon-toxic salt thereof.
 3. The compound according to claim 1, wherein Gis a nitrogen atom, an oxygen atom or a sulfur atom, and J is a carbonatom, or a non-toxic salt thereof.
 4. The compound according to claim 1,wherein G is a carbon atom, and J is a nitrogen atom, an oxygen atom ora sulfur atom, or a non-toxic salt thereof.
 5. The compound according toclaim 1, wherein the ring A is a C5-10 mono- or bi-carbocyclic ring, ora non-toxic salt thereof.
 6. The compound according to claim 1, whereinthe ring A is a 5- to 10-membered mono- or bi-heterocyclic ring having 1to 5 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom, or anon-toxic salt thereof.
 7. The compound according to claim 1, whereinthe ring B is a C5-10 mono- or bi-carbocyclic ring, or a non-toxic saltthereof.
 8. The compound according to claim 1, wherein the ring B is a5- to 10-membered mono- or bi-heterocyclic ring having 1 to 5 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or a sulfur atom, or a non-toxic saltthereof.
 9. The compound according to claim 1, which is (1)1-(2,6-dichlorophenyl)-5-benzylpiperidin-2-one, (2)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (3)1-(2,6-dichlorophenyl)-5-(2-naphtylmethyl)piperidin-2-one, (4)1-(2,6-dichlorophenyl)-5-(2,4-dimethylbenzyl)piperidin-2-one, (5)1-(2,6-dichlorophenyl)-5-(4-trifluoromethoxybenzyl)piperidin-2-one, (6)1-(2,6-dichlorophenyl)-5-(4-trifluoromethylbenzyl)piperidin-2-one, (7)1-(2,6-dichlorophenyl)-5-(3,5-difluorobenzyl)piperidin-2-one, (8)1-(2,6-dichlorophenyl)-5-(2-chlorobenzyl)piperidin-2-one, (9)1-(2,6-dichlorophenyl)-5-(4-fluorobenzyl)piperidin-2-one, (10)1-(2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one, (11)1-(2,6-dichlorophenyl)-5-(1-naphtylmethyl)piperidin-2-one, (12)1-(2,6-dichlorophenyl)-5-(2-methoxybenzyl)piperidin-2-one, (13)1-(2,6-dichlorophenyl)-5-(4-ethylbenzyl)piperidin-2-one, (14)1-(2,6-dichlorophenyl)-5-benzylpiperidin-2-one, (15)1-(2-chlorophenyl)-5-benzylpiperidin-2-one, (16)1-(2,6-difluorophenyl)-5-benzylpiperidin-2-one, (17)1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (18)1-[2,6-dichloro-4-(1,1,1-triphenylmethoxymethyl)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one,(19)1-(2,6-dichloro-4-hydroxymethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(20) 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenoxy)piperidin-2-one, (21)1-(2,6-dichlorophenyl)-5-(2,4-difluorothiophenoxy)piperidin-2-one, (22)1-(2,6-dichloro-4-nitrophenyl)-5-benzylpiperidin-2-one, (23)1-(2,6-dichloro-4-nitrophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(24) 1-(2,6-dichloro-4-aminophenyl)-5-benzylpiperidin-2-one, (25)1-(2,6-dichloro-4-aminophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(26)1-[2,6-dichloro-4-(N-(4-methylimidazol-5-ylmethyl)amino)phenyl]-5-benzylpiperidin-2-one,(27)1-[2,6-dichloro-4-(N-(4-methylamino)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(28)1-[2,6-dichloro-4-(2-phenylacetylamino)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one,(29)1-(2,6-dichloro-4-acetylaminophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(30)1-[2,6-dichloro-4-(N-methyl-2-phenylacetylamino)phenyl]-5-(2,4-difluorobenzyl)piperidin-2-one,(31)(3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(32) (3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(33) (3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-ethylpiperidin-2-one,(34) (3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-ethylpiperidin-2-one,(35)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methoxymethylpiperidin-2-one,(36) 1-(2,6-dichlorophenyl)-5,5-bis(2,4-difluorobenzyl)piperidin-2-one,(37)1-(4-bromo-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(38) 1-(2-methylnaphthalen-1-yl)-5-(2,4-difluorobenzyl)piperidin-2-one,(39)1-(2,6-dimethylphenyl-5-(2-methoxyethoxymethoxybenzyl)piperidin-2-one,(40) 1-(2,6-dichlorophenyl)-5-(4-nitrobenzyl)piperidin-2-one, (41)1-(2,6-dichlorophenyl)-5-(2-cyanobenzyl)piperidin-2-one, (42)1-(2,6-dimethylphenyl 5-(2-bromobenzyl)piperidin-2-one, (43)1-(thiazol-2-yl)-5-(2,4-difluorobenzyl)piperidin-2-one, (44)1-(2,6-dichlorophenyl)-5-(2-methoxymethoxymethylbenzyl)piperidin-2-one,(45)1-(4-t-butoxycarbonylamino-2-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(46)1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(47)1-(3-t-butoxycarbonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(48)1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one,(49) 1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (50)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-5-hydroxymethylpiperidin-2-one,(51)1-(2,6-dimethylphenyl)-5-(3-phenylprop-1-enyl)-5-hydroxymethylpiperidin-2-one,(52)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(53)1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(54)3-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-1,3-tetrahydroxazin-2-one,(55)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-4-acetylpiperazin-2-one,(56) 4-(2,6-dichlorophenyl)-6-(2,4-difluorobenzyl)morpholin-3-one, (57)1-(2,6-dichlorophenyl)-5-((2,4-difluorophenyl)hydroxymethyl)piperidin-2-one,(58)1-(4-t-butoxycarbonylamino-2,6-dichlorophenyl)-5-((2,4-difluorophenyl)hydroxymethyl)piperidin-2-one,(59)1-(4-bromo-2,6-dichlorophenyl)-5-((2-thienyl)hydroxymethyl)piperidin-2-one,(60)1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorophenyl)hydroxymethyl)piperidin-2-one,(61) 1-(2,6-dichlorophenyl)-5-(2-phenylethyl)piperidin-2-one, (62)1-cyclohexyl-5-(2,4-difluorobenzyl)piperidin-2-one, (63)1-(2-(2-hydroxyethyl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (64)1-(3,5-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (65)(5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (66)(5S)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one, (67)(3R,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(68) (3R,5R)-1-(4-nitro-2,6-dimethylphenyl5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one, (69)(3R,5R)-1-(4-bromo-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(70)(3S,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-(benzyloxycarbonylamino)piperidin-2-one,(71)(3S,5R)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl-3-aminopiperidin-2-one,(72)(5S)-1-(2,6-dimethylphenyl)-5-(2,4-difluorophenylsulfonylamino)piperidin-2-one,(73)1-(4-(3-ethoxycarbonylpropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(74)1-(4-(3-carboxypropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(75)1-(4-(4-hydroxybutylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(76)1-(4-(2-(ethoxycarbonyl)ethylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(77)1-(4-(2-carboxyethylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(78)1-(4-(3-hydroxypropylcarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(79)1-(4-methanesulfonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(80)1-(2,6-dichloro-4-(pyrrolidin-2,5-dion-1-yl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(81)1-(2,6-dichloro-4-(piperidin-2,6-dion-1-yl)phenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(82)1-(4-t-butylcarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(83)1-(4-methoxycarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(84)1-(4-(N,N-diethylamino)methylcarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(85)1-((4-(1-methylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one,(86)1-(4-((1-acetylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(87)1-(4-(2-hydroxybenzyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(88)1-(4-((2-methylimidazol-4-yl)methylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(89)1-(4-((1-t-butoxycarbonylpiperidin-4-yl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(90)1-(4-(piperidin-4-ylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(91)1-(4-(1-methanesulfonylpiperidin-4-ylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(92)1-(4-ethylaminocarbonylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(93)1-(4-(N,N-dimethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(94)1-(4-((2S)-2-(t-butoxycarbonylamino)-3-benzyloxypropanoylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(95)1-(4-((2S)-2-(t-butoxycarbonylamino)-3-hydroxypropanoylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(96)1-(4-(L-serylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(97)1-(4-(L-tyrosylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(98)1-(4-(L-asparaginylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(99)1-(4-(N-(pyridin-2-ylmethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one,(100)1-(4-(pyridin-2-ylmethylamino)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one,(101)1-(4-(N-ethoxycarbonylmethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(102)1-(4-ethoxycarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(103)1-(4-carboxymethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(104)1-(4-(N-carboxymethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(105)1-(4-(N-(2-hydroxyethyl)-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(106)1-(4-(2-hydroxyethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(107)1-(4-(N-aminocarbonylmethyl-N-t-butoxycarbonylamino)-2,6-dichlorophenyl)-(2,4-difluorobenzyl)piperidin-2-one,(108)1-(4-aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(109)1-(4-(N,N-dimethylamino)carbonylmethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(110)1-(4-methylaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(111)1-(4-(4-methylpiperadin-1-ylcarbonylmethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(112)1-(4-(N,N-dimethylamino)aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(113)1-(4-aminoaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(114)1-(4-(2-hydroxyethylamino)carbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(115)1-(4-t-butylaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(116)1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(117)1-(4-benzyloxyaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(118)1-(4-hydroxyaminocarbonylmethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(119)1-(4-(3-(N,N-dimethylamino)propyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(120)1-(4-(2-oxo-1,3-oxazolidin-3-yl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(121)1-(4-(N-(2-(N′,N′-dimethylamino)ethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(122)1-(4-(2-(N,N-dimethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(123)1-(4-(2-(morpholin-4-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(124)1-(4-(2-(N,N-diethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(125)1-(4-(2-(piperidin-1-yl)ethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(126)1-(4-(2-(imidazol-1-yl)ethylamino)-2,4-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one,(127)1-(4-(2-pyrrolidin-1-yl)ethylamino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(128)1-(4-(2-(4-methylpiperadin-1-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(129)1-(4-(N-(2-aminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(130)1-(4-(2-methanesulfonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(131)1-(4-(N-(2-methylcarbonylaminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(132)1-(4-(2-methylcarbonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(133)1-(4-(N-(2-aminocarbonylaminoethyl)-N-(t-butoxycarbonyl)amino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(134)1-(4-(2-aminocarbonylaminoethyl)amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(135)1-(4-(2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(136) 1-(3-amino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(137)1-(3-methylcarbonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(138)1-(3-methanesulfonylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperdin-2-one,(139)1-(3-ethoxycarbonylmethylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(140)1-(3-carboxylmethylamino-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(141)1-(3-(2-hydroxyethylamino)-6-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(142)1-(4-(2-(N,N-dimethylamino)ethyl)amino-2,6-dichlorophenyl)-5-(2-fluorobenzyl)piperidin-2-one,(143) 1-(2,6-dichlorophenyl)-5-(4-aminobenzyl)piperidin-2-one, (144)1-(2,6-dichlorophenyl)-5-(4-cyclohexylcarbonylaminobenzyl)piperidin-2-one,(145)1-(2,6-dichlorophenyl)-5-(4-methylcarbonylaminobenzyl)piperidin-2-one(146) 1-(4-amino-2-chlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(147) 1-(2,6-dichlorophenyl)-5-(2-hydroxymethylbenzyl)piperidin-2-one,(148) 1-(2,6-dichlorophenyl)-5-(2-aminomethylbenzyl)piperidin-2-one,(149)1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonylaminomethylbenzyl)piperidin-2-one,(150)1-(2,6-dichlorophenyl)-5-(2-benzylaminocarbonylaminomethylbenzyl)piperidin)-2-one,(151)1-(2,6-dichlorophenyl)-5-(2-phenylaminocarbonylaminomethylbenzyl)piperidin-2-one,(152)1-(2,6-dichlorophenyl)-5-(2-cyclohexylaminocarbonylaminomethylbenzyl)piperidin-2-one,(153)1-(2,6-dichlorophenyl)-5-(2-(3-trifluoromethylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one,(154)1-(2,6-dichlorophenyl)-5-(2-ethylaminocarbonylaminomethylbenzyl)piperidin-2-one,(155)1-(2,6-dichlorophenyl)-5-(2-(3-methylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one,(156)1-(2,6-dichlorophenyl)-5-(2-(2-trifluoromethylphenyl)aminocarbonylaminomethylbenzyl)piperidin-2-one,(157)1-(2,6-dichlorophenyl)-5-(2-methylcarbonylamomethylbenzyl)piperidin-2-one,(158)1-(2,6-dichlorophenyl)-5-(2-(3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)aminocarbonylaminomethylbenzyl)piperidin-2-one,(159)1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonyloxymethylbenzyl)piperidin-2-one,(160) 1-(2,6-dichlorophenyl)-5-(2-formylbenzyl)piperidin-2-one, (161)1-(2,6-dichlorophenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one,(162)1-(2,6-dichlorophenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one,(163)1-(2,6-dichlorophenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonyl)ethylpiperidin-2-one,(164) 1-(2,6-dimethylphenyl)-5-(2-hydroxybenzyl)piperidin-2-one, (165)1-(2,6-dimethylphenyl)-5-(2-isobutyloxybenzyl)piperidin-2-one, (166)1-(2,6-dimethylphenyl)-5-(2-ethoxycarbonylmethoxybenzyl)piperidin-2-one,(167) 1-(2,6-dimethylphenyl)-5-(2-carboxymethoxybenzyl)piperidin-2-one,(168)1-(2,6-dimethylphenyl)-5-(2-(1-methyl-3-t-butylpyrazol-5-yl)aminocarbonylmethyloxyphenylmethyl)piperidin-2-one,(169)1-(4-methoxycarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(170)1-(4-carboxyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(171)1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(172)1-(4-(3-(N,N-dimethylamino)propylaminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(173)1-(4-methylaminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(174)1-(4-(N,N-dimethylamino)carbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(175)1-(4-(morpholin-4-yl)carbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(176)1-(4-(4-methylpiperazin-1-yl)carbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(177)1-(4-(3-ethoxycarbonylpropyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(178)1-(4-(2-ethoxycarbonylethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(179)1-(4-(3-carboxypropyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(180)1-(4-(2-carboxyethyl)aminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(181)1-(4-(t-butoxycarbonyl)amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(182)1-(4-amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(183)1-(4-aminomethyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(184)1-(4-(4-(tetrahydropyran-2-yloxy)but-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(185)1-(4-(4-hydroxybut-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(186)1-(4-(4-(N,N-dimethylamino)but-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(187)1-(4-(4-morpholinobut-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(188)1-(4-(4-(4-methylpiperazin-1-yl)but-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(189)1-(4-(4-(N,N-dimethylamino)butyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(190)(E)-1-(4-(2-(2-(N,N-dimethylamino)ethyl)vinyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(191)1-(4-(5-hydroxypent-1-ynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(192)1-(4-(5-hydroxypentyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(193)1-(4-(4-formylbutyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(194)1-(4-(4-carboxylbutyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(195)(E)-1-(4-(2-(methoxycarbonyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(196)(E)-1-(4-(2-(carboxyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(197)1-(4-methoxycarbonyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(198)1-(4-carboxyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(199)1-(4-(2-(N,N-dimethylamino)ethyl)aminocarbonyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(200)1-(4-(N,N-dimethylamino)methyl-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(201)1-(4-(4-methylpiperazin-1-ylmethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(202)1-(4-piperazin-1-yl)-2,6-dichlorophenyl)-5-(2,6-difluorobenzyl)piperidin-2-one,(203)1-(4-(4-methylpiperazin-1-yl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(204)1-(4-(3-hydroxy-1-propinyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(205)1-(4-(3-(N,N-dimethylamino)propyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(206)1-(4-(3-aminopropyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(207)1-(4-(4-hydroxybut-1-ynyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(208)1-(4-(4-(N,N-dimethylamino)butyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(209)(E)-1-(4-(2-(methyloxycarbonyl)vinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(210)(E)-1-(4-(2-aminocarbonylvinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(211)(E)-1-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(212)1-(4-(2-cyanoethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(213)1-(4-(2-methoxycarbonylethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(214)1-(4-(2-methylaminocarbonyl)ethyl)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(215)(3R,5R)-1-(4-methoxycarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(216)(3R,5R)-1-(4-carboxy-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(217)(3R,5R)-1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(218)(3R,5R)-1-(4-(3-(N,N-dimethylamino)-1-propynyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(219)(3R,5R)-1-(4-(3-(N,N-dimethylamino)propyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(220)1-(4-carboxyl-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(221)1-(4-t-butyloxycarbonylamino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(222)1-(4-amino-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(223)1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)-2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)tetrahydropyrimidin-2(1H)-one,(224) 1-(2,6-dimethylphenyl)-5-(2-methoxycarbonylbenzyl)piperidin-2-one,(225) 1-(2,6-dimethylphenyl)-5-(2-carboxybenzyl)piperidin-2-one, (226)1-(2,6-dimethylphenyl)-5-(2-(2-methoxycarbonylvinyl)benzyl)piperidin-2-one,(227)(3R,5R)-1-(4-amino-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(228)(3R,5R)-1-(4-(t-butoxycarbonylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(229)(3R,5R)-1-(4-(2-(N,N-dimethylamino)ethylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(230) 1-(2,6-dimethylphenyl)-5-(3-phenylpropyl)piperidin-2-one, (231)(3RS,5RS)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-hydroxypiperidin-2-one,(232)(3RS,5SR)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-hydroxypiperidin-2-one,(233)(3RS,5RS)-1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(234)(3RS,5SR)-1-(2,6-dimethylphenyl)-5-(2,4-difluorobenzyl)-3-methylpiperidin-2-one,(235)(5S)-1-(2,6-dimethylphenyl)-5-(methyl(2,4-difluorophenylsulfonyl)amino)piperidin-2-one,(236)(5S)-1-(2,6-dimethylphenyl)-5-((2-hydroxyethyl)(2,4-difluorophenylsulfonyl)amino)piperidin-2-one,(237)1-(4-(N-methylcarbonyl-N-methylamino)-2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperidin-2-one,(238)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-3-methyltetrahydropyrimidin-2(1H)-one,(239) 1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)piperazin-2-one,(240)1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzyl)-4-methylpiperazin-2-one,(241)1-(2,6-dichlorophenyl)-5-(2,4-difluorophenylcarbonyl)piperidin-2-one,(242)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-hydroxyethyl)piperidin-2-one,(243)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)vinyl)piperidin-2-one,(244)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)ethyl)piperidin-2-one,(245)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)1-hydroxyiminomethyl)piperidin-2-one,(246)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-methoxymethyl)piperidin-2-one,(247)1-(2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)-1-chloromethyl)piperidin-2-one,(248)(5E)-1-(2,6-dichlorophenyl)-5-(2,4-difluorobenzylidene)piperidin-2-one,(249)(5E)-1-(4-bromo-2,6-dichlorophenyl)-5-(2,4-difluorobenzylidene)piperidin-2-one,(250)1-(4-amino-2,6-dichlorophenyl)-5-(1-(2,4-difluorophenyl)1-hydroxyiminomethyl)piperidin-2-one,(251) 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenylamino)piperidin-2-one,or a non-toxic salt thereof.
 10. A pharmaceutical composition, whichcomprises the piperidin-2-one derivative compound represented by formula(I) according to claim 1, or a non-toxic salt thereof, as an activeingredient.
 11. A method for inhibiting p38MAP kinase, which comprisesadministering to a mammal an effective amount of the piperidin-2-onederivative compound represented by formula (I) according to claim 1, ora non-toxic salt thereof.
 12. A method for preventing and/or treatingvarious inflammatory diseases, rheumatoid arthritis, osteoarthritis,arthritis, osteoporosis, autoimmune diseases, infectious diseases,sepsis, cachexia, cerebral infarction, Alzheimer's disease, asthma,chronic pulmonary inflammatory diseases, reperfusion injury, thrombosis,glomerulonephritis, diabetes, graft versus host rejection, inflammatorybowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis,tumor growth and metastasis, multiple myeloma, plasma cell leukemia,Castleman's disease, atrial myxoma, psoriasis, dermatitis, gout, adultrespiratory distress syndrome (ARDS), arteriosclerosis,post-percutaneous transluminal coronary angioplasty (PTCA) restenosis orpancreatitis, which comprises administering to a mammal an effectiveamount of the piperidin-2-one derivative compound represented by formula(I) according to claim 1, or a non-toxic salt thereof.